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Yiqi Fumai lyophilized injection (YQFM), a compound traditional Chinese medicine prescription derived from "Sheng Mai Powder," is approved for the treatment of cardiovascular diseases. YQFM is usually prescribed in combination with some Western medicines to treat patients, such as aspirin, nifedipine, and clopidogrel. However, the herb-drug interactions (HDIs) of YQFM are still unclear. We determined the effect of YQFM on drug metabolism-related CYP450 enzymes by in vitro assays. And the effects of YQFM on the pharmacokinetics of aspirin, nifedipine, or clopidogrel were analyzed in rats, as well as the effect of YQFM on the prothrombin time of aspirin or clopidogrel, to evaluate the safety and efficacy of co-administration. Our study indicated that the clinical dose of YQFM did not significantly influence the relevant CYP450 isoenzymes. Besides, YQFM had no effect on the pharmacokinetics of aspirin, nifedipine, or clopidogrel single and multiple administrations in rats. In pharmacodynamics study, YQFM also had no impact on prothrombin time of aspirin or clopidogrel. Based on the results of pharmacogenomics, pharmacokinetics, and pharmacodynamics, the HDIs of YQFM have a good safety profile, and the combination with the above three drugs might have synergistic effects due to the different efficacy of YQFM-quality markers., (© 2024 John Wiley & Sons Ltd.)

Piperine has been reported to inhibit the enzyme activity of cytochrome P450 (CYP) 3A4. The aim of this study was to develop and validate a physiologically based pharmacokinetic (PBPK) model for piperine and to predict potential food-drug interactions (FDIs) between piperine and CYP3A4 substrate drugs using these models. The PBPK model for piperine was successfully developed and validated. Using this model, FDIs with ten CYP3A4 substrate drugs were simulated. The predicted area under the curve (AUC) ratios (with and without piperine, following a 7-day intake of 20 mg/day) for six drugs were found to exceed 1.25, with significant increases in AUC observed for ritonavir (31%), nifedipine (34%), cyclosporine (35%), triazolam (36%), alfentanil (39%), and simvastatin (59%) in humans. These findings suggest that caution should be exercised when consuming amounts of black pepper equivalent to a daily intake of 20 mg piperine during treatment with CYP3A4 substrate drugs, as it may significantly alter their pharmacokinetics.

Objective: This study aimed to analyze the pharmacokinetic (PK) characteristics, safety, and bioequivalence (BE) of a test (T) preparation of a nifedipine controlled-release tablet and the reference (R) drug (Adalat GTIS) in Chinese study participants in the context of fasting and postprandial states., Materials and Methods: An open-label, single-center, randomized, single-dose, two-period study was designed including two separate arms, one with administration under fasting conditions and one with administration under postprandial conditions (high-fat, high-calorie breakfast). After oral administration, the nifedipine concentrations in plasma were quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at regular intervals. Primary PK parameters, including the area under the concentration curve from 0 to infinity (AUC 0-∞ ), the area under the concentration profile from 0 to the last measurable concentration time (AUC 0-t ), and maximal measured plasma concentration (C max ) were log-transformed with BE limits of 80 - 125% to evaluate BE. All adverse events (AEs) were wholly supervised., Results: The PK profiles of the T and R formulations were comparable to each other under both fasting and postprandial conditions. The 90% confidence intervals (CIs) of the AUC 0-∞ , AUC 0-t , and C max were 92.69 - 106.06%, 93.32 - 107.05%, and 99.53 - 116.71%, respectively, under the fasting state. The 90% CIs of the AUC 0-∞ , AUC 0-t , and C max were 105.05 - 117.40%, 105.43 - 117.82%, and 102.66 - 116.30%, respectively, in the postprandial arm. 47 cases of drug-associated AEs were noted in the entire research., Conclusion: Under both the fasting and postprandial states, the two nifedipine controlled-release formulations were bioequivalent and safe in healthy Chinese subjects.

This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CL tot ) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t 1/2 ) and volume of distribution at steady state (V dss ) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

The aim of this study was to develop and evaluate the transdermal patch formulations of nifedipine. The patch formulations containing nifedipine were prepared and optimized with different ratios of vinyl and cellulose-derived polymers, drug contents, and permeation enhancers. Among the various formulations, the patch formulation containing a 1:5 ratio of ethyl cellulose and polyvinyl pyrrolidone was selected for ex vivo pharmacokinetic study based on in vitro permeation studies using stratum corneum of the pig's skin. The cumulative percentage release after the transdermal administration of the optimized patch formulation was 71.43%, and the plasma concentration of nifedipine was maintained for 16 hrs. The physicochemical evaluation study including flatness, thickness, moisture content and uptake, drug content in vitro release, and ex vivo permeation indicated satisfactory results. The formulation batch with clove oil as a penetration enhancer has shown better ex vivo permeation as compared to the formulations without enhancers and another synthetic enhancer. These results suggest that the optimized patch formulation Q3 could be further developed for clinical applications, providing the therapeutic plasma level of nifedipine over an extended period. Hence analyzing the results of the evaluation tests, in vitro and ex vivo data on the preparation and optimization of nifedipine-loaded transdermal patch, it can be concluded that the formulation shows its feasibility as an effective transdermal delivery system for nifedipine.

Nifedipine is a potent antihypertensive medication classified as a dihydropyridine calcium channel blocker. The objective of this trial was to assess the bioequivalence of a 30-mg nifedipine controlled-release tablet and a reference drug in a cohort of healthy Chinese individuals. Two independent open-label, randomized, single-dose, crossover studies were conducted, 1 under fasting conditions (N = 44, with 1 participant dropping out midway) and the other under fed conditions (N = 44, with 4 participants dropping out midway). Plasma concentrations of nifedipine were determined using liquid chromatography-mass spectrometry, and pharmacokinetic (PK) parameters were calculated using noncompartmental analysis with Phoenix WinNonlin 8.0 software. In both fasting and fed studies, reasonable bioequivalence was observed for the PK parameters of both the test product and the reference drug. A good safety profile was demonstrated for both the test product and reference drug, with no serious adverse events reported, and both were similarly well tolerated. An important observation with food coadministration was that systemic exposure to nifedipine (based on area under the curve, AUC 0-∞ ) was reduced by approximately 12%. The bioequivalence of the test product and reference drug under fasting/fed conditions in healthy subjects in China was demonstrated by the study results., (© 2024, The American College of Clinical Pharmacology.)

Nifedipine is used for treating mild to severe hypertension and preventing preterm labor in pregnant women. Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal-placental-fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22. Model parametrization involved scaling nifedipine transplacental clearance based on Caco-2 permeability, and fetal hepatic clearance was obtained from in vitro to in vivo extrapolation encompassing cytochrome P450 3A7 and 3A4 activities. Predicted concentration profiles were compared with in vivo observations and the transplacental transfer results were evaluated using 2-fold criteria. The PBPK model predicted a mean cord-to-maternal plasma ratio of 0.98 (range, 0.86-1.06) at term, which agrees with experimental observations of 0.78 (range, 0.59-0.93). Predicted nifedipine exposure was 1.4-, 2.0-, and 3.0-fold lower at 15, 27, and 39 weeks of gestation when compared with nonpregnant exposure, respectively. This innovative PBPK model can be applied to support maternal and fetal safety assessment for nifedipine at various stages of pregnancy., (© 2024, The American College of Clinical Pharmacology.)

Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms in vivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug-drug interactions (DDIs) exist between a PPI, omeprazole, and nifedipine extended-release formulations, where systemic exposure of nifedipine was increased in subjects after multiple-dose pretreatment of omeprazole. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well-understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically-based pharmacokinetic (PBPK) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to characterize the potential impact of pH. The PBPK models incorporated two-stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4-mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH-dependent formulation. The reported model-based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The aim of this study was to evaluate the bioequivalence of generic nifedipine controlled-release tablet compared to branded product under fasting and fed conditions. A randomized, single-dose, 2-period, crossover study with a 7-day washout period was performed in 84 healthy Chinese volunteers (fasting cohort, n = 42; fed cohort, n = 42). In each study period, volunteers were assigned to receive a single oral dose of the generic or reference product (30 mg). Blood samples were collected before dosing and up to 72 hours after administration. The plasma concentration of nifedipine was determined by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained using a noncompartmental model and log-transformed pharmacokinetic parameters (maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity) were used to evaluate bioequivalence. The results showed that the 90% confidence interval for the geometric mean ratio of pharmacokinetic parameters of the test and reference products ranged from 80.0% to 125.0% in both the fasting and fed cohorts, meeting the criteria for bioequivalence. No serious adverse events were reported throughout the study and no adverse events led to withdrawal from the study. Food effects were found in both the test and reference products, with mean maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity increased by 23.7%, 20.7%, and 20.5%, respectively, for the test product and 35.2%, 13.4%, and 14.7% for the reference product after a high-fat and high-calorie breakfast., (© 2023, The American College of Clinical Pharmacology.)

Oral extended-release (ER) dosage forms have been used to sustain blood drug levels, reduce adverse events, and improve patient compliance. We investigated potential effects of comedication on pharmacokinetic exposure of nifedipine ER products with different formulation designs and manufacturing processes. A clinical study compared a generic version of nifedipine ER tablet with pH-dependent dissolution behavior with an osmotic pump product with pH independent drug release under fasting condition. In this study, two nifedipine tablet products were tested with or without short-term omeprazole comedication in healthy subjects. Seven-day administration of omeprazole before nifedipine dosing significantly increased the gastric pH, and subsequently increased the geometric least square (LS) means of area under the concentration-time curve from time zero to the last measurable timepoint (AUC 0-t ) and maximum plasma concentration (C max ) of nifedipine to 132.6% (90% confidence interval (CI): 120.6-145.7%) and 112.8% (90% CI: 100.8-126.3%) for pH-dependent ER tablets, and 120.6% (90% CI: 109.7-132.5%) and 122.5% (90% CI: 113.7-131.9%) for the pH-independent ER tablets, respectively. Similar extent of increase in AUC 0-t and C max was confirmed in the subpopulations whose gastric pH was ≥ 4 or ≤ 3 in subjects with or without omeprazole administration. Given that similar increases in drug exposures were observed for both pH-dependent and pH-independent nifedipine formulations and the geometric LS mean ratios were between 112% and 133% with and without short-term omeprazole comedication, the gastric pH may have limited effects on omeprazole-induced nifedipine PK changes on the tested formulations. The inhibition of cytochrome P450 3A4 activity may play a significant role causing nifedipine exposure changes for both formulations, which would warrant additional assessment., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension. The 3-week SMS treatment increased the systemic exposure to nifedipine by nearly two-fold and decreased nifedipine clearance by 39% in rats. Among the ingredients of SMS component herbs, schisandrin B, schisantherin A, and methylophiopogonanone A, inhibited the nifedipine oxidation (NFO) activities of rat hepatic and intestinal microsomes, as well as human CYP3A4. Methylophiopogonanone A was identified as a time-dependent inhibitor of CYP3A4. After 1:5 propensity score matching, 4,894 patients with nifedipine/felodipine use were analyzed. In patients receiving nifedipine/felodipine, the subgroup with concurrent SMS treatment had a higher incidence of headache (92.70 per 1,000 personyears) than the subgroup without SMS treatment (51.10 per 1,000 person-years). There was a positive association between headache incidence and cumulative doses of SMS (1-60 g SMS: hazard ratio (HR): 1.39; 95% confidence interval (CI): 1.11-1.74; >60 g SMS: HR: 1.97; 95% CI: 1.62-2.39; p < 0.0001). However, patients who had higher cumulative SMS doses had a lower risk of all-cause mortality (1-60 g SMS: HR: 0.67; 95% CI: 0.47-0.94; >60 g SMS: HR: 0.54; 95% CI: 0.37-0.79; p = 0.001). Results demonstrated increased rat plasma nifedipine levels after 3-week SMS treatment and increased headache incidence should be noted in nifedipine/felodipine-treated patients with prolonged SMS administration.

Purpose: The intestinal fluid pH is maintained by the bicarbonate buffer system that shows unique properties regarding drug dissolution. Nevertheless, current compendial dissolution tests use phosphate buffers. The purpose of the present study was to investigate the effect of bicarbonate and phosphate buffers on the dissolution profiles of amorphous solid dispersions (ASD) composed of ionizable polymers., Methods: Hydroxypropylmethylcellulose acetate succinate (HPMCAS), amino methacrylate copolymer (AMC), and hydroxypropylmethylcellulose (HPMC) were employed as acidic, basic, and neutral polymers, respectively. Nifedipine (NIF) was used as a model drug. Dissolution profiles were measured in pH 6.5 bicarbonate and phosphate buffers by a mini-scale paddle dissolution test. The pH of bicarbonate buffers was maintained by the floating lid method., Results: The pH change of the bicarbonate buffer was suppressed to less than + 0.25 pH for 3 h by the floating lid method. In all cases, the NIF concentration was supersaturated against the solubility of crystalline NIF. The dissolution rates of HPMCAS and AMC ASDs were 1.5 to 2.0-fold slower in the bicarbonate buffer than in the phosphate buffer when compared at the same buffer capacity. The dissolution profile of HPMC ASD was not affected by the buffer species. The higher the buffer capacity and ionic strength, the faster the dissolution rate of HPMCAS ASD., Conclusion: The dissolution rate of ASDs with ionizable polymers would be overestimated by using unphysiological phosphate buffer solutions. It is important to use a biorelevant bicarbonate buffer solution for dissolution testing., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The aim of this study was to formulate osmotic pump capsules (OPCs) to control the release of nifedipine (NP). NP solid dispersion was prepared by solvent evaporation method. The prepared mixture of NP solid dispersion and various excipients were filled into the commercial HPMC hard capsule shells and then coated with cellulose acetate (CA) solution to form NP-OPC. The CA coating solution consisted of CA as semi-permeable membrane, and Poloxamer 188 as pore formers. The impact of addition agents, citric acid and pore formers on in vitro drug release were investigated. Furthermore, the study has highlighted the impact of paddle speed and the pH value of release media, on the release and compared the release with the commercial controlled release tablets. The in vitro drug release study indicated that drug release could reach 95% in 24 h with optimal formulation, and interestingly model fitting showed that the drug release behavior was closely followed to zero-order release kinetics. The pharmacokinetic studies were performed in rabbits with commercial controlled release tablets as reference, both preparations showed a sustained release effect. Compared with traditional preparation methods of OPCs, the new preparation process was simplified without the operation of laser drilling and the sealing process of capsule body and cap, which improved the feasibility of industrial production., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In the present era of drug development, quantification of drug concentrations following pharmacokinetic studies has preferentially been performed using plasma as a matrix rather than whole blood. However, it is critical to realize the difference between measuring drug concentrations in blood versus plasma and the consequences thereof. Pharmacokinetics using plasma data may be misleading if concentrations differ between plasma and red blood cells (RBCs) because of differential binding in blood. In this review, factors modulating the partitioning of drugs into RBCs are discussed and the importance of determining RBC uptake of drugs for drug candidate selection is explored. In summary, the choice of matrix (plasma vs whole blood) is an important consideration to be factored in during drug discovery.

Background and Objectives: Proton pump inhibitors (PPIs) can affect the intragastric release of other drugs from their dosage forms by elevating the gastric pH. They may also influence drug absorption and metabolism by interacting with P-glycoprotein or with the cytochrome P450 (CYP) enzyme system. Nifedipine is a Biopharmaceutics Classification System (BCS) class II drug with low solubility across physiologic pH and high permeability. Previous studies have demonstrated that drug-drug interaction (DDI) existed between omeprazole and nifedipine with significantly increased systemic exposure of nifedipine in subjects after pre-treatment for 7 days with omeprazole compared to the subjects without omeprazole treatment. It was shown that omeprazole not only induced an increase in intragastric pH, but also inhibited the CYP3A4 activity, while CYP3A4-mediated oxidation is the main metabolic pathway of nifedipine. The purpose of this study is to apply a physiologically based pharmacokinetic (PBPK) modeling approach to investigate the DDI mechanism for an immediate release formulation of nifedipine with omeprazole., Methods: A previously published model for omeprazole was modified to integrate metabolites and to update CYP inhibition based on the most updated published in vitro data. We simulated the nifedipine pharmacokinetics in healthy subjects with or without the multiple-dose pretreatment of omeprazole (20 mg) following oral administrations of immediate-release (IR) (10 mg) nifedipine. Nifedipine solubility at different pHs was used to simulate the nifedipine pharmacokinetics for both clinical arms. Multiple sensitivity analyses were performed to understand the impact of gastric pH and the CYP3A4-mediated gut and liver first pass metabolism on the overall nifedipine pharmacokinetics., Results: The developed PBPK model properly described the pharmacokinetics of nifedipine and predicted the inhibitory effect of multiple-dose omeprazole on CYP3A4 activity. With the incorporation of the physiologic effect of omeprazole on both gastric pH and CYP3A4 to the PBPK model, the verified PBPK model allows evaluating the impact of the increase in gastric pH and/or CYP3A4 inhibition. The simulated results show that the nifedipine metabolic inhibition by omeprazole may play an important role in the DDI between nifedipine and omeprazole for IR nifedipine formulation., Conclusion: The developed full PBPK model with the capability to simulate DDI by considering gastric pH change and metabolic inhibition provides a mechanistic understanding of the observed DDI of nifedipine with a PPI, omeprazole.

We investigated the gastrointestinal absorption characteristics of oral sustained-release formulations in microminipigs, dogs, and monkeys in order to clarify the similarities in absorption properties between these animals and humans. Time profiles of oral absorption of nifedipine and valproic acid were calculated from the plasma concentration-time profiles of the drugs by a deconvolution method. The curves for both drugs in microminipigs were close to or slightly higher than those in humans, whereas those in monkeys were lower. Furthermore, the plasma concentration-time profiles of the drugs were subjected to non-compartmental analysis. The fractions of a dose absorbed into the portal vein (FaFg) in microminipigs ranged from 50 to 100% of the human values, whereas those in monkeys were less than half the human values. In addition, the other absorption-related parameters for the sustained-release formulation in microminipigs, as well as monkeys, were comparable to those in humans. In conclusion, the oral absorption properties of microminipigs and humans were similar regarding the sustained-release formulations. Therefore, microminipig is a suitable animal model to estimate the oral absorption of sustained-release formulations in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug-drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug-drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice., Methods: A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9-21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated., Results: Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC 0-48h and C max of nifedipine by 83% (90% confidence interval [CI] 1.46-2.31) and 64% (90% CI 1.34-2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC 0-t and C max of S-warfarin by 92% (90% CI 1.68-2.18) and 24% (90% CI 1.10-1.39), respectively., Conclusion: Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug-drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates., Competing Interests: Quan-Ren Wang and Si-Yuan Mao are employees of Jiangsu Hengrui Medicine Co., Ltd. The authors report no other conflicts of interest in this work., (© 2020 Zhu et al.)

Nifedipine is one of calcium channel blockers that commonly used clinically to treat hypertension and angina in Egyptian patients. A sustained-release (SR) formulation of nifedipine is available in the Egyptian community and administered twice daily. This study aimed to to compare the pharmacokinetics and safety profiles of a 20 mg SR and IR (immediate release) formulation of nifedipine after single-dose administration in healthy Egyptian subjects. Randomized, crossed open-label two- way clinical trial, in 16 healthy adult volunteers, of 24.75±5.20 years, with BMI 23.26±1.756 were assessed. Blood samples were collected at predefined times for 48 h and analyzed for Nifedipine plasma concentrations using validated reversed phase liquid chromatography method with ultraviolet detection. Pharmacokinetics was determined using non- compartmental model pharmacokinetics and analyzed using one-way ANOVA (P≤0.05). Following a single oral administration, SR formulation had a lower C max , compared to IR formulation (54.46±17.75 , 107.45±29.85 ng/mL, respectively), and T max was significantly longer (2.97 vs. 1.13 h) for the SR and IR formulation, respectively. There was no significant difference between the SR and the IR formulations for AUC 0-last and AUC 0-∞ (326.7±98.28 vs. 309.27±105.53 ng·h·mL -1 and 380.9 ± 105.24 vs. 334.36±108.1 ng·h·mL -1 , respectively). SR formulation of nifedipine showed similar pharmacokinetics to the IR Formulation (F%=1.049), but it additionally allows a less frequent administration. Therefore, The nifedipine SR and IR formulations were well tolerated and displayed comparable safety profiles., Competing Interests: The authors state no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

We investigated the impact of short-acting and extended release nifedipine on sympathetic activity using radiotracer methodology in patients with stable coronary artery disease in order to more accurately document the response of the sympathetic nervous system to different formulations of this dihydropyridine calcium channel antagonist. Participants were randomized to placebo, short-acting or extended release nifedipine for 7-10 days. On the final day, systemic blood pressure, cardiac filling pressures, cardiac output, plasma norepinephrine (NE) and total body NE spillover were measured at baseline (time 0) and repeated at intervals for 6 hours. There were no differences in baseline measures between groups. Following the morning dose of study medication there were no changes in hemodynamics or sympathetic activity in the placebo group. However, there was a significant fall in blood pressure and a significant increase in total body NE spillover in both nifedipine groups. Importantly, the increase in sympathetic activity in response to short-acting nifedipine began earlier (30 minutes) and was much greater than that observed in the extended release group, which occurred later (270 minutes). These findings confirm that sustained therapy with nifedipine is associated with activation of the sympathetic nervous system which is dependent on the pharmacokinetics of the formulation.

Proliposomes were used to improve the solubility and oral bioavailability of nifedipine. Nifedipine proliposomes were prepared by methanol injection-spray drying method. The response surface method was used to optimize formulation to enhance the encapsulation efficiency (EE%) of nifedipine. The particle size of nifedipine proliposomes after rehydration was 114 nm. Surface morphology of nifedipine proliposomes was observed by a scanning electron microscope (SEM) and interaction of formulation ingredients was assessed by differential scanning calorimetry (DSC). The solubility of nifedipine is improved 24.8 times after forming proliposomes. In vitro release experiment, nifedipine proliposomes had a control release effect, especially in simulated gastric fluid. In vivo, nifedipine proliposomes significantly improved the bioavailability of nifedipine. The area under the concentration-time curve (AUC 0 - ∞ ) of nifedipine proliposomes was about 10 times than nifedipine after oral administration. The elimination half-life (T 1/2 β ) of nifedipine was increased from 1.6 h to 6.6 h. In conclusion, proliposomes was a promising system to deliver nifedipine through oral route and warranted further investigation., Competing Interests: The authors declare no conflicts of interest.

Background: A combinational therapy is mostly preferred in hypertension treatment because of low-dose and less side effects like pretibial edema, and gastrointestinal bleeding., Objective: So the objective of the present work was to formulate an advanced drug delivery system in the form of bio-responsive microneedles by incorporating nifedipine, a cardiodepressant and diltiazem, a vasodilator for effective synergism in the treatment of hypertension., Methods: The pH-responsive PLGA nanospheres of diltiazem were formulated using Water-in-Oil-in- Water (W/O/W) double emulsion and solvent-diffusion-evaporation technique. These nanospheres were added to nifedipine-PVP mixture and then incorporated into mold to develop microneedles., Results: The microneedles showed the release of nifedipine almost 96.93± 2.31% for 24 h due to high PVP solubilization. The nanospheres of diltiazem on contact with acidic pH of skin managed to form of CO2 bubbles and increase the internal pressure to burst PLGA shell due to pore formation. The mean blood pressure observed for the normal group was 89.58 ± 3.603 mmHg, whereas the treatment with the new formulation significantly reduced the mean blood pressure up to 84.11 ± 2.98 mmHg in comparison to the disease control group (109.9 ± 1.825 mm Hg)., Conclusion: This system co-delivers the drugs nifedipine and diltiazem in hypertension and shows an advance alternative approach over conventional drug delivery system., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Co amorphous systems are supersaturated drug delivery systems which offer a basic platform for delivery of multicomponent adducts (combination of more than one active pharmaceutical ingredient (API)) and/or as a fixed dose combination therapy, in addition to their potential to improve the apparent solubility, dissolution rate and ultimately bioavailability of poorly water soluble APIs. In the present work, a new drug-drug co amorphous system namely valsartan-nifedipine was prepared by quench cooling technique. Prepared co amorphous system was characterized for its solid state behavior with the help of Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X Ray Diffractometry (PXRD). The optimized co amorphous system was stable for 1 month when exposed to accelerated stability condition (40 ± 2 °C and 75 ± 5% RH). The improved stability of amorphous nifedipine in co amorphous system was attributed to improved miscibility and intra and intermolecular non-covalent interactions mainly due to presence of hydrogen bonding between valsartan and nifedipine which was studied by FTIR analysis. Co amorphous systems were evaluated by mainly in vitro dissolution and in vivo benefit. In vitro dissolution study showed nearly 5.66 folds and 1.61 folds improvement which was translated to 3.63 and 2.19 times enhancement in vivo C max for nifedipine and valsartan respectively., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Herein, the purpose of this study is to evaluate the effects of kaempferol on bioavailability and pharmacokinetics of nifedipine and its metabolite dehydronifedipine in rats. The experimental design is based on with or without kaempferol in the oral and intravenous administration of nifedipine in rats. Moreover, the pharmacokinetic parameters including nifedipine and dehydronifedipine were evaluated in rats.The in vitro studies ofkaempferol were investigated on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity. Kaempferol reduced a 50% inhibitory concentration (IC 50 ) of 8.6 μmol·L -1 on CYP3A4 enzyme activity. Moreover, kaempferol clearly improved the cell internalization of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Depending on increased concentrations of kaempferol, the areas under the plasma concentration-time curve (AUC 0-∞ ) and the peak concentration (C max ) of nifedipine were increased after oral and intravenous administration. Moreover, the absolute bioavailability (AB) and relative bioavailability (RB) of nifedipine in the presence of kaempferol was significantly higher than those of the control group after oral and intravenous administration. Improvement of bioavailability of nifedipine by kaempferol may be mainly because of the inhibition of the P-gp-mediated efflux transporter in the small intestine and CYP3A4-mediated metabolism in the small intestine or liver, or both., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Aims: This study explores the impact of paediatric patient related factors and choice of formulation on the dissolution characteristics of nifedipine and lorazepam, 2 drug substances regularly applied in very young patients and in compounded formulations., Methods: Dissolution experiments were designed to reflect clinical practice in a paediatric hospital, with respect to dosage forms, feeding regimens and methods of administration. Solubility studies addressed the influence of age and prandial state. Drug solubility and dissolution experiments were conducted in biorelevant media and adapted age-specific (neonate and infant) media. Dissolution studies were performed with the mini-paddle apparatus and the flow-through cell apparatus., Results: Dissolution of nifedipine formulations was not affected by age-related changes of the fasted state simulated gastrointestinal fluids, and by disintegration of the formulation before administration. However, a significant difference in nifedipine's dissolution rate from commercial tablets and compounded capsules was observed. The dissolution of lorazepam tablets was affected by fasted- vs fed-state media, but it was deemed less likely to be clinically relevant. The significant effect of fed-state media on nifedipine's solubility was considered to have possible clinical relevance since very young patients are almost continuously in a fed state., Conclusion: The in vitro results obtained from these studies reveal the potential of biorelevant solubility and dissolution studies reflecting clinical practice to predict drug performance in paediatric patients., (© 2019 The British Pharmacological Society.)

Nifedipine and nicardipine loaded PLGA extrudates have a great potential to prevent cerebral vasospasms after subarachnoid hemorrhage or surgical clipping of aneurysm. A constant release over approx. two weeks is desired. Although in vivo studies on humans have been reported, there is limited knowledge about the release kinetics and the underlying mechanisms. Therefore, nifedipine and nicardipine loaded PLGA implants with different drug loads were manufactured by extrusion and investigated. In addition to the measurements of the release kinetics, GPC, DSC, X-ray diffraction and light microscopic investigations were performed for a detailed characterization. The water uptake and polymer erosion studies showed an initial lag phase of 5-7 days and an acceleration of both processes thereafter. With 5% loaded implants a higher drug release compared to 10% drug loaded polymers could be achieved and not only the relative amount of drug release (% of loaded drug), but surprisingly also the absolute amount of the released drug increased. The drugs were initially in an amorphous state. For nifedipine, formation of drug crystals with time has been observed by light microscopy and X-ray diffraction. The analysis of the drug content in the degrading polymer showed a very large increase from 10% to about 20% (nifedipine) and over 50% (nicardipine). In contrast, no or only a moderate increase of the drug content occurred for initially 5% loaded polymer implants. We postulate that water penetration and polymer degradation induced changes of the microenvironment lead to supersaturated systems. A supersaturated state is faster reached for polymers with higher drug load and therefore, drug precipitation takes place at earlier time points. As a result, drug release might be incomplete for poorly soluble drugs and paradoxically, the total amount of drug release might be higher for systems with a lower drug load. Drug release is initially controlled by the PLGA matrix, but later by the dissolution kinetics of the precipitated drug which are very slow for poorly soluble drugs according to the Noyes-Whitney equation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nifedipine, a known substrate to breast cancer resistance protein (ABCG2/BCRP), is used for the treatment of hypertension during breastfeeding. This study aimed to evaluate the effect of ABCG2 c.421C>A on nifedipine transfer to breast milk (BM) in hypertensive women. Nineteen hypertensive breastfeeding women treated with 20 mg nifedipine every 12 hours were investigated. Blood and BM samples were collected simultaneously 15-30 days after delivery and at least 15 days after drug treatment. Patients genotyped as ABCG2 c.421CC showed nifedipine plasma and BM concentrations ranging from 8.32-178.1 ng/mL and 4.8-58.5 ng/mL, respectively. ABCG2 c.421C>A showed a trend towards significance (p = 0.0793) on nifedipine in BM, with concentrations approximately 3 times higher in the heterozygous 421 CA (29 ng/mL) in comparison to 421 CC (10.5 ng/mL). Nifedipine BM/plasma ratio was significantly lower in 421CC when compared to 421CA (p = 0.01). In conclusion, ABCG2 c.421C>A polymorphism is associated with higher transfer of nifedipine to BM., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Deformable liposomes (DL) are successfully exploited to enhance the skin penetration of several compounds. Nevertheless, the "soft" nature of the bilayer favors the drug leakage, mainly in the case of hydrophobic compounds. This work aimed to develop a suitable strategy to stabilize the lipid bilayer, without compromising the deformability properties of DL. The approach relied on the design of a "matryoshka" system, namely a drug in micelles in deformable liposomes (DiMiL) system. The performances (drug leakage, deformability and in vitro skin penetration profile) of DiMiLs were tested using nifedipine and piroxicam as model compounds and compared to those of traditional DL. The micelles were made of Kolliphor HS15 whereas the lipid vesicles were composed of egg-phosphatidylcholine and Tween 80 (T80) at 95:5 or 85:15 w/w ratios. As expected, the drug leakage from DL was high after only one month of storage (almost 50% in the case of nifedipine and in the range of 39-79% in the case of piroxicam loaded DL, depending on T80 content). Optimized DiMiL formulations retained instead the drug content up to two-months storage period. Moreover, the constant of deformability of DiMiLs felt in the acceptance range for deformable vesicles intended for cutaneous application and the skin permeated amount of the delivered drugs was increased of at least 4 times. In conclusion, DiMiL reveals to be a suitable approach to avoid the leakage of hydrophobic compounds and an attractive transdermal drug delivery system for poorly permeable drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The purpose of the current study was to prepare nifedipine (NF) loaded-PLGA nanoparticles (NPs) using two different methods (nanoprecipitation method (N-2) and emulsion-solvent evaporation method (N-4)) to achieve the sustained release of NF and to reduce its side effects, and also to investigate the in vitro characteristics of NPs (surface morphology, particle size and size distribution, encapsulation efficiency and in vitro release characteristics). SEM images of nanoparticles revealed their approximate spherical shape. The mean particle sizes of the prepared nanoparticles ranged from 294.27±7.93 to 424.92±4.96 nm with almost neutral zeta potential values (close to 0 mV). The percent encapsulation efficiency values of N-2 and N-4 formulations 13.03±1.82% and 18.96±1.95% (p=0.05), respectively. The extents of cumulative drug release from N-2 and N-4 in PB pH 7.4 medium were up to about 100 % in 38 days and 22 days, respectively (when comparing two formulations, p<0.05). PLGA nanoparticles are useful systems for the sustained release of NF, and hence for reducing its side-effects and increasing patient compliance.

In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products., (Published by Elsevier Inc.)

The traditional Chinese herbal formula Shenmai-Yin (SY) and nifedipine have both been used to treat patients with cardiovascular disorders. Nifedipine is primarily oxidized by cytochrome P450 (CYP) 3A. The oxidation and pharmacokinetics of nifedipine were studied in rats in vitro and in vivo to illustrate the interaction of SY with nifedipine. Schisandrol A, schisandrin A and schisandrin B were identified as the main lignans in SY. In the study in vitro, the ethanolic extract of SY was used due to the solubility and the extract inhibited nifedipine oxidation (NFO) activity in a time-dependent manner. Among lignans, schisandrin B caused the most potent inhibition. According to the time-dependent inhibition behavior, rats were treated with SY 1 h before nifedipine administration. After oral treatment with 1.9 g/kg SY, nifedipine clearance decreased by 34% and half-life increased by 142%. SY treatment decreased hepatic NFO activity by 49%. Compared to the change caused by ketoconazole, the SY-mediated reduction of nifedipine clearance was moderate. These findings demonstrate that SY causes a time-dependent inhibition of NFO and schisandrin B contributes to the inhibition. The decreased nifedipine clearance by SY in rats warrants further human study to examine the clinical impact of this decrease., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Nifedipine is a Biopharmaceutics Classification System class II drug displaying large variability in absorption even when administered as immediate-release soft gelatin capsules of a cosolvent formulation. This in vitro study sought to understand the reasons behind variability in nifedipine absorption, how it can be minimized, and if it can be predicted using in vitro models. A dynamic in vitro simulated stomach duodenum model was used to explore drug concentration-time profiles of nifedipine soft gelatin capsules under conditions simulating how patients take their medicines. Specifically, the effect of prandial gastric emptying patterns and fluid volume administration (250 mL vs. 50 mL water) were investigated. Significant supersaturation of nifedipine was observed. While administration of large and small water volumes gave rise to a similar C max and area under the curve (AUC ∞ ), the coefficient of variation in AUC was 4.8% and 49%, respectively, which can be attributed to differences in precipitation kinetics. Fasting and fed gastric emptying patterns also gave rise to a similar AUC; however, C max was significantly lower in the fed state. These trends are consistent with previously published in vivo results in healthy volunteers. The simulated stomach duodenum provides a good discriminative screening tool for predicting trends in drug concentration profiles of Biopharmaceutics Classification System class II drugs., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Nifedipine is completely absorbed by the gastrointestinal tract and its pharmacokinetics and metabolism may be influenced by microorganisms. If gut microbes are involved in the metabolism of nifedipine, plateau hypoxia may regulate the bioavailability and the therapeutic effect of nifedipine by altering the metabolic activity of the gut microbiota. We herein demonstrated for the first time that gut flora is involved in the metabolism of nifedipine by in vitro experiments. In addition, based on the results of 16S rRNA analysis of feces in rats after acute plateau, we first confirmed that the plateau environment could cause changes in the number and composition of intestinal microbes. More importantly, these changes in flora could lead to a slower metabolic activity of nifedipine in the body after an acute plateau, resulting in increased bioavailability and therapeutic efficacy of nifedipine. Our research will provide basis and new ideas for changes in the fecal flora of human acutely entering the plateau, and contribute to rational drug use of nifedipine.

1. A physiologically based pharmacokinetic (PBPK) model that includes inhibition constant evaluated in cryopreserved hepatocytes was used to predict drug-drug interactions (DDIs) between orally administered nifedipine, a CYP substrate, and fluconazole or ketoconazole, CYP inhibitors, in rats. 2. The Kp,uu, ratio of unbound inhibitor concentration in liver ([I]liver,u) to that in plasma ([I]sys,u), of fluconazole and ketoconazole was 1.0 and 13.0, indicating that ketoconazole accumulates in liver. The ratios of inhibition constants in rat liver microsomes (Ki,mic,u) to that in rat cryopreserved hepatocytes (Ki,hep,u) for fluconazole and ketoconazole were 1.5 and 25.5, which were similar to the Kp,uu and suggested that cryopreserved hepatocytes could mimic the hepatic accumulation of inhibitors. 3. The increases in AUC of nifedipine predicted by the minimal PBPK model using [I]liver,u/Ki,mic,u and [I]sys,u/Ki,hep,u were within 1.5-fold of the observed values for both inhibitors, whereas the model using [I]sys,u/Ki,mic,u underestimated the AUC increase caused by ketoconazole 21-fold. 4. These results indicated that hepatic accumulation factor of an inhibitor is required for a precise DDI projection and that cryopreserved hepatocytes would be useful to obtain the Ki including hepatic accumulation factor. It was demonstrated that PBPK model using Ki,hep,u could be a valuable approach for quantitative DDI projection.

Background: Physiologically based pharmacokinetic modeling is considered a valuable tool for predicting pharmacokinetic changes in pregnancy to subsequently guide in-vivo pharmacokinetic trials in pregnant women. The objective of this study was to extend and verify a previously developed physiologically based pharmacokinetic model for pregnant women for the prediction of pharmacokinetics of drugs metabolized via several cytochrome P450 enzymes., Methods: Quantitative information on gestation-specific changes in enzyme activity available in the literature was incorporated in a pregnancy physiologically based pharmacokinetic model and the pharmacokinetics of eight drugs metabolized via one or multiple cytochrome P450 enzymes was predicted. The tested drugs were caffeine, midazolam, nifedipine, metoprolol, ondansetron, granisetron, diazepam, and metronidazole. Pharmacokinetic predictions were evaluated by comparison with in-vivo pharmacokinetic data obtained from the literature., Results: The pregnancy physiologically based pharmacokinetic model successfully predicted the pharmacokinetics of all tested drugs. The observed pregnancy-induced pharmacokinetic changes were qualitatively and quantitatively reasonably well predicted for all drugs. Ninety-seven percent of the mean plasma concentrations predicted in pregnant women fell within a twofold error range and 63% within a 1.25-fold error range. For all drugs, the predicted area under the concentration-time curve was within a 1.25-fold error range., Conclusion: The presented pregnancy physiologically based pharmacokinetic model can quantitatively predict the pharmacokinetics of drugs that are metabolized via one or multiple cytochrome P450 enzymes by integrating prior knowledge of the pregnancy-related effect on these enzymes. This pregnancy physiologically based pharmacokinetic model may thus be used to identify potential exposure changes in pregnant women a priori and to eventually support informed decision making when clinical trials are designed in this special population.

This paper presents the results of zeta potential, water contact angle, atomic force microscopy image, in vitro solubility, and content of heavy metals in polylactic acid (PLA)/chitosan (CS) nanoparticles loading nifedipine. In addition, the In Vivo test of the PLA/CS nanoparticles loading nifedipine in the mice is also one of highlights of this work. The Zeta potential result shows that the charged surface of the PLA/CS nanoparticles loading nifedipine is neutral, negative or complex depending on nifedipine content. Nifedipine plays a role in increase of hydrophobic property, swelling degree and regular surface as well as decrease of surface rough of the nanoparticles. The PLA/CS/nifedipine nanoparticles are dissolved in the solutions with pH 6.8, pH 4.5 and pH 1.2. The In Vivo test of PLA/CS nanoparticles loading nifedipine on mice was evaluated by the change in diastolic pressure, systolic pressure, arterial pressure and heart rate. The obtained results confirm that the PLA/CS nanoparticles loading nifedipine is suitable to apply in the treatment of hypertension patients lately.

Anal fissure is common and painful disease of anorectum. In this study, microparticles containing nifedipine and lidocaine HCl were prepared by spray drying and applied to bio-degradable and bio-stable tampons. Characterization of microparticles was determined by visual analyses, mass yield, particle size measurement, encapsulation efficiency, drug loading and in vitro drug release. Mass yield was between 5.5 and 45.9%. The particle size was between 15.1 and 26.8 µm. Encapsulation efficiency were 96.142 ± 5.931 and 85.571 ± 3.301; drug loading were 65.261 ± 3.914% and 37.844 ± 4.339% of L2 and N1, respectively. Well-separated, mainly spherical microparticles with suitable properties were obtained. Optimum microparticles were applied to tampons. Physical properties and visual characteristics of tampons were investigated before and after binder application. In vitro drug release from tampons were also examined. According to the results, textile-based carrier systems loaded microparticles containing nifedipine and lidocaine HCl will be an effective and promising alternative for current anal fissure treatment.

Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro-in vivo relationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for C max and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13-1.29) and 1.09 (90%CI, 1.02-1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which C max and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81-3.38) and 1.57 (90%CI, 1.43-1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Diabetes mellitus can inhibit cytochrome P450 3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women., Methods: The study was conducted in 12 hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20 mg, 12/12 h). On the 34th week of gestation, serial blood samples were collected (0-12 h) after administration of the medication. At delivery, samples of maternal and fetal blood and amniotic fluid were collected for determination of nifedipine distribution in these compartments., Results: The median pharmacokinetic parameters of CG were: peak plasma concentration (C max ) 26.41 ng ml -1 , time to reach C max (t max ) 1.79 h, area under the plasma concentration vs. time curve from 0-12 h (AUC 0-12 ) 235.99 ng.h ml -1 , half-life (t½) 4.34 h, volume of distribution divided by bioavailability (Vd/F) 560.96 l, and Cl T /F 84.77 l h -1 . The parameters for T2DM group were: C max 23.52 ng ml -1 , t max 1.48 h, AUC 0-12 202.23 ng.h ml -1 , t½ 5.00 h, Vd/F 609.40 l, and apparent total clearance (Cl T /F) 98.94 l h -1 . The ratios of plasma concentrations of nifedipine in the umbilical vein, intervillous space and amniotic fluid to those in the maternal vein for CG and T2DM were 0.53 and 0.44, 0.78 and 0.87, respectively, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. The ratios of plasma concentrations in the umbilical artery to those in the umbilical vein were 0.82 for CG and 0.88 for T2DM., Conclusions: There was no influence of T2DM on the pharmacokinetics or placental transfer of nifedipine in hypertensive women with controlled diabetes., (© 2017 The British Pharmacological Society.)

Comparing modified-release formulations can be difficult using current bioequivalence criteria. Two 60-mg-once-daily nifedipine formulations are deemed bioequivalent in Canada. This study examined the validity of the assumption that these interchangeable, but different, delivery technologies are therapeutically equivalent in maintaining systolic blood pressure (SBP) control throughout the entire dosing interval. We used 24-h Ambulatory Blood Pressure Monitoring to objectively examine whether formulation switches changed population SBP >2 mmHg (reflecting 6% increased stroke mortality) and in what proportion of patients SBP changed ≥6 mmHg (risking unnecessary therapeutic alterations). When 20 patients, previously receiving 60-mg-once-daily Nifedipine-GITS, were switched to Mylan-Nifedipine-XL, population-mean ± SE 24-h SBP increased 3 ± 1.1 mmHg (P = 0.0173) and 8-h nocturnal SBP increased 4 ± 1.6 mmHg (P = 0.0098). Thus, interchange of nifedipine formulations can affect therapeutic consistency. These data support existing calls to improve criteria for establishing bioequivalence between formulations employing differing modified-release technologies., (© 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs., Objective: Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor., Study Design: We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice., Results: Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect., Conclusion: Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus., (Copyright © 2016. Published by Elsevier Inc.)

Objective: To investigate the pharmacokinetic (PK) profiles and safety of nifedipine and candesartan after a single oral dose of nifedipine gastrointestinal therapeutic system (GITS) 30 mg/candesartan cilexetil 8 mg (N30/C8 mg) fixed-dose combination (FDC) in adults with mild to moderate hepatic impairment., Methods: A phase I, single-center, non-randomized, non-controlled, non-blinded, observational study (N = 32). PK profiles for nifedipine and candesartan were assessed in patients with mild (Child-Pugh A; group 1) or moderate (Child-Pugh B; group 2) hepatic impairment and compared with age- and gender-matched healthy controls (groups 3 and 4) following a single dose of N30/C8 FDC. Safety and tolerability were assessed throughout the study., Results: On average, area under the plasma concentration vs. time curves (AUC) for nifedipine increased 93% and 253% in mild and moderate hepatic impairment, while maximum plasma concentrations (C max ) increased 64% and 171%, respectively. AUC values for candesartan increased 19% and 92%, while C max values increased 3% and 11%, respectively. In subjects with or without liver impairment, adverse event rates were similar and consistent with the known side-effect profiles of nifedipine GITS and candesartan as monotherapies., Conclusions: Careful monitoring, and, if necessary, dose adjustment according to response and tolerability may be required for nifedipine GITS/candesartan FDC in patients with mild and moderate hepatic impairment.
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Cytochrome P450 (CYP) 3A accounts for nearly 30% of the total CYP enzymes in the human liver and participates in the metabolism of over 50% of clinical drugs. Moreover, CYP3A plays an important role in chemical metabolism, toxicity, and carcinogenicity. New animal models are needed to investigate CYP3A functions, especially for drug metabolism. In this report, Cyp3a1/2 double knockout (KO) rats were generated by CRISPR-Cas9 technology, and then were characterized for viability and physiological status. The Cyp3a1/2 double KO rats were viable and fertile, and had no obvious physiological abnormities. Compared with the wild-type (WT) rat, Cyp3a1/2 expression was completely absent in the liver of the KO rat. In vitro and in vivo metabolic studies of the CYP3A1/2 substrates indicated that CYP3A1/2 was functionally inactive in double KO rats. The Cyp3a1/2 double KO rat model was successfully generated and characterized. The Cyp3a1/2 KO rats are a novel rodent animal model that will be a powerful tool for the study of the physiological and pharmacological roles of CYP3A, especially in drug and chemical metabolism in vivo.

Monoolein cubosomes containing either spironolactone (SPI) or nifedipine (NI) were prepared using a high-pressure homogenization technique and characterized in terms of their solubility and oral bioavailability. The mean particle size, polydispersity index (PDI), zeta potential, solubility and encapsulation efficiency (EE) values of the SPI- and NI-loaded cubosomes were determined to be 90.4 nm, 0.187, -13.4 mV, 163 µg/mL and 90.2%, and 91.3 nm, 0.168, -12.8 mV, 189 µg/mL and 93.0%, respectively, which were almost identical to those of the blank cubosome. Small-angle X-ray scattering analyses confirmed that the SPI-loaded, NI-loaded and blank cubosomes existed in the cubic space group Im3̄m. The lattice parameters of the SPI- and NI-loaded cubosomes were 147.6 and 151.6 Å, respectively, making them almost identical to that of blank cubosome (151.0 Å). The in vitro release profiles of the SPI- and NI-loaded cubosomes showed that they released less than 5% of the drugs into various media over 12-48 h, indicating that most of the drug remained encapsulated within the cubic phase of their lipid bilayer. Furthermore, the in vivo pharmacokinetic results suggested that these cubosomes led to a considerable increase in the systemic oral bioavailability of the drugs compared with pure dispersions of the same materials. Notably, the stability results indicated that the mean particle size and PDI values of these cubosomes were stable for at least 4 weeks. Taken together, these results demonstrate that monoolein cubosomes represent promising drug carriers for enhancing the solubility and oral bioavailability of poorly water-soluble drugs.

Objectives: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success., Methods: Simcyp Simulator, GastroPlus ™ and GI-Sim were used. Compounds with published Biowaiver monographs (bisoprolol (BCS I), nifedipine (BCS II), cimetidine (BCS III), furosemide (BCS IV)) were selected to ensure availability of accurate and reproducible data for all required parameters. Simulation success was evaluated with the average fold error (AFE) and absolute average fold error (AAFE). Parameter sensitivity analysis (PSA) to selected parameters was performed., Key Findings: Plasma concentration-time profiles after intravenous administration were forecast within an AAFE < 3. The addition of absorption processes resulted in more variability in the prediction of the plasma profiles, irrespective of biopharmaceutics classification system (BCS) class. The reliability of literature permeability data was identified as a key issue in the accuracy of predicting oral drug absorption., Conclusion: For the four drugs studied, it appears that the forecasting accuracy of the PBPK models is related to the BCS class (BCS I > BCS II, BCS III > BCS IV). These results will need to be verified with additional drugs., (© 2016 Royal Pharmaceutical Society.)

Purpose: AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior., Methods: Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution (R d ) and absorption (R a ) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a (R dth and R ath ) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds., Results: The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased., Conclusion: A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs., Competing Interests: Shinya Uchida and Tsutomu Kotegawa have received advisory fees from KUREHA CORPORATION.

A nanoemulsion drug delivery system was developed to increase the oral bioavailability of mebudipine as a calcium channel blocker with very low bioavailability profile. The impact of nano-formulation on the pharmacokinetic parameters of mebudipine in rats was investigated. Nanoemulsion formulations containing ethyl oleate, Tween 80, Span 80, polyethylene glycol 400, ethanol and deionized water were prepared using probe sonicator. The optimum formulation was evaluated for physicochemical properties, such as particle size, morphology and stability. The particle size of optimum formulation was 22.8 ± 4.0 nm. Based on the results of this study, the relative bioavailability of mebudipine nanoemulsion was enhanced by about 2.6-, 2.0- and 1.9-fold, respectively, compared with suspension, ethyl oleate solution and micellar solution. In conclusion, nanoemulsion is an interesting option for the delivery of poorly water soluble molecules, such as mebudipine.

The purpose of this study was to investigate the possible effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The effects of pioglitazone on P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 activities were also evaluated. Nifedipine was mainly metabolized by CYP3A4. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administrations of nifedipine to rats in the presence and absence of pioglitazone (0.3 and 1.0 mg/kg). Pioglitazone inhibited the CYP3A4 enzyme activity in a concentration-dependent manner. Inhibitory concentration (IC50) was 12.1 μM. In addition, pioglitazone significantly increased the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The areas under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (C max) of nifedipine were significantly increased by 52.1 and 59.1 %, respectively, in the presence of pioglitazone (1.0 mg/kg) compared with control group. The total body clearance (CL/F) of nifedipine was significantly (1.0 mg/kg) decreased by pioglitazone (35.8 %). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of pioglitazone (1.0 mg/kg) was significantly higher (25.3 %) than that of the control. The metabolite-parent AUC ratio (MR) in the presence of pioglitazone (1.0 mg/kg) significantly decreased (23.9 %) compared to that of the control group. The increased bioavailability of nifedipine in the presence of pioglitazone may be due to an inhibition of the P-gp-mediated efflux transporter in the small intestine and to the inhibition of the metabolism by inhibition of CYP3A4 in the small intestine and/or the liver, and/or to a reduction of CL/F of nifedipine by pioglitazone.

To investigate the relationship between the pharmacokinetics (PK) and effects and/or side-effects of nifedipine and propranolol, simultaneous examination of their PK and pharmacodynamics (PD), namely blood pressure (BP), heart rate (HR), and QT interval (QT), were assessed in spontaneously hypertensive rats as a disease model. Drugs were infused intravenously for 30 min, then plasma PK and hemodynamic effects were monitored. After general two-compartmental analysis was applied to the plasma data, PD parameters were calculated by fitting the data to PK-PD models. After nifedipine administration, the maximal hypotensive effect appeared about 10 min after starting the infusion, then BP started to elevate although the plasma concentration increased, supposedly because of a negative feedback mechanism generated from the homeostatic mechanism. After propranolol administration, HR decreased by half, and this bradycardic effect was greater than that with nifedipine. Wide variation in QT was observed when the propranolol concentration exceeded 700 ng/mL. This variation may have been caused by arrhythmia. Prolongation of QT with propranolol was greater than that with nifedipine, and bradycardia was slower than the concentration increase and QT prolongation. The characteristically designed PK-PD model incorporating a negative feedback system could be adequately and simultaneously fitted to both observed effect and side-effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Context: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility., Objective: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution., Materials and Methods: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves., Results: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram., Discussion: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting., Conclusion: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

With the increased reliance on in vitro dissolution testing as an indicator of in vivo drug behavior and the trend towards the in silico modeling of dosage form performance, the need for bioperformance dissolution methodology development has been enhanced. Determination of the in vivo drug delivery profile is essential for the bioperformance dissolution test development and in vitro/in vivo correlation modeling, as well as the understanding of absorption mechanisms. The aim of this study was to compare different methods in terms of their usefulness and applicability in deciphering in vivo delivery of nifedipine administered in modified release dosage forms. A detailed survey of publications on nifedipine pharmacokinetics was done and used to identify the magnitude of food effect. In vitro dissolution testing was performed under various experimental conditions. Obtained results indicate the potential for using the developed in silico model coupled with discriminative in vitro dissolution data for identification of the in vivo drug product behavior.