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Fuzi, an effective common herb, is often combined with Gancao to treat disease in clinical practice with enhancing its efficacy and alleviating its toxicity. The major toxic and bioactive compounds in Fuzi and Gancao are aconitine (AC) and glycyrrhizic acid (GL), respectively. This study aims to elucidate detoxification mechanism between AC and GL from pharmacokinetic perspective using physiologically based pharmacokinetic (PBPK) model. In vitro experiments exhibited that AC was mainly metabolized by CYP3A1/2 in rat liver microsomes and transported by P‐glycoprotein (P‐gp) in Caco‐2 cells. Kinetics assays showed that the Km and Vmax of AC towards CYP3A1/2 were 2.38 μM and 57.3 pmol/min/mg, respectively, whereas that of AC towards P‐gp was 11.26 μM and 147.1 pmol/min/mg, respectively. GL markedly induced the mRNA expressions of CYP3A1/2 and MDR1a/b in rat primary hepatocytes. In vivo studies suggested that the intragastric and intravenous administration of GL significantly reduced systemic exposure of AC by 27% and 33%, respectively. Drug–drug interaction (DDI) model of PBPK predicted that co‐administration of GL would decrease the exposure of AC by 39% and 45% in intragastric and intravenous dosing group, respectively. The consistency between predicted data and observed data confirmed that the upregulation of CYP3A1/2 and P‐gp was the crucial detoxification mechanism between AC and GL. Thus, this study provides a demonstration for elucidating the compatibility mechanisms of herbal formula using PBPK modeling and gives support for the clinical co‐medication of Fuzi and Gancao. Aconitine (AC) and glycyrrhizic acid (GL) are selected to elucidate the detoxification mechanism of Fuzi‐Gancao herbal pair. In vitro experiments found that AC was a victim of CYP3A1/2 and P‐glycoprotein (P‐gp), and GL was their inducer. In vivo studies suggested that GL reduced AC exposure. Developed PBPK models validated interaction between AC and GL, which confirmed the role of CYP3A and P‐gp in detoxification mechanism between AC and GL, thus providing support for clinical co‐medication of Fuzi and Gancao. [ABSTRACT FROM AUTHOR]

Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8‐fold) and oral administration (2.4‐fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A‐modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26‐fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P =.08). Intravenous midazolam CL did not significantly differ between the 2 groups (P =.93). Moreover, the metabolic ratio of midazolam to 1′‐hydroxy midazolam did not differ between the 2 groups for both oral administration (P =.67) and intravenous administration (P =.26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam. [ABSTRACT FROM AUTHOR]

Crizotinib is a tyrosine kinase inhibitor used to treat anaplastic lymphoma kinase-positive lung cancer. There is in vitro evidence that crizotinib may auto-inhibit cytochrome P450 3A (CYP3A) activity, with important implications for crizotinib pharmacokinetics. In order to test whether crizotinib treatment alters CYP3A activity in vivo, mice were treated with 5 and 25 mg/kg crizotinib (p.o.) daily for 14 days. Results showed that crizotinib treatment did not alter CYP3A activity as determined by erythromycin N-demethylation. In addition, CYP3A polypeptide expression as measured by Western blot was unchanged. Therefore, our results do not support CYP3A inhibition by crizotinib in vivo. [ABSTRACT FROM AUTHOR]

1. To investigate cytochrome P450 3A (CYP3A)-mediated metabolism in vivo, plasma concentrations of triazolam (TRZ) are often monitored as a CYP3A marker in CYP3A-humanised mice. However, it has not been determined whether plasma concentrations of TRZ after intravenous administration can reflect hepatic CYP3A activity in CYP3A-humanised mice. 2. Firstly, we investigated the pharmacokinetics of TRZ in wild-type and Cyp3a-knockout (Cyp3a-KO) mice. Plasma concentration profiles of TRZ and α-hydroxy (OH) TRZ were very similar in wild-type and Cyp3a-KO mice. On the other hand, AUC of 4-OH TRZ in Cyp3a-KO mice was significantly lower than that in wild-type mice. Pregnenolone 16α-carbonitrile (PCN) decreased the areas under the plasma concentration-time curves (AUCs) of TRZ and α-OH TRZ in both groups. There was no significant effect of PCN on AUC of 4-OH TRZ in Cyp3a-KO mice. 3. Next, we verified that AUC of 4-OH TRZ in CYP3A-humanised mice was higher than that in Cyp3a-KO mice, although the difference was not significant. 4. In conclusion, plasma concentrations of 4-OH TRZ, but not those of TRZ and α-OH TRZ, might reflect hepatic CYP3A activity in mice in vivo. These results provide important insights for in vivo studies using a CYP3A-humanised model. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effects of multiple doses of baicalin (BG) on the pharmacokinetics of ciclosporin (CsA) in rats and the potential mechanisms. Methods: Pharmacokinetic parameters of CsA were determined in male rats after administration of CsA (3 mg/kg, i.g. or i.v.) to rats in the presence and absence of BG (80 mg/kg, i.g. or i.v.) for 7 days. The livers and intestines of rats were isolated and the CYP3A and p‐glycoprotein (P‐gp) expression were analysed. The effect of BG on the intestinal absorptive behaviour of CsA was also investigated using in‐vitro everted rat gut sac model. Key findings: Baicalin (80 mg/kg, i.v., 7 days) had no effect on the intravenously administered CsA. However, BG (80 mg/kg, i.g., 7 days) significantly decreased the Cmax, AUC0–t and AUC0–∞ of orally administered CsA by 38, 26 and 25%, respectively (P < 0.01 or P < 0.05). Further study revealed that the expression of P‐gp in intestine increased in oral multiple doses of BG‐treated rats. The in‐vitro everted rat gut sac model demonstrated BG (10 μm) significantly decreased the absorption of CsA (10 μm) in intestine (P < 0.05). Conclusions: Multiple doses of BG decreased the oral bioavailability of CsA in rats significantly, which may be mainly attributable to inhibition of absorption of CsA in intestine and induction of P‐gp. The interaction between BG and CsA may occur when BG and CsA were co‐administered for long‐term use. The dosage adjustment and blood concentration monitoring of CsA may be required in clinic. [ABSTRACT FROM AUTHOR]

Adagrasib (Krazati™) is the second FDA-approved specific KRASG12C inhibitor for non-small cell lung cancer (NSCLC) patients harboring this mutation. The impact of the drug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing enzymes CYP3A and carboxylesterase 1 (CES1) on the pharmacokinetics of oral adagrasib were studied using genetically modified mouse models. Adagrasib was potently transported by human ABCB1 and modestly by mouse Abcg2 in vitro. In Abcb1a/b -/- and Abcb1a/b;Abcg2 -/- mice, the brain-to-plasma ratios were enhanced by 33- and 55-fold, respectively, compared to wild-type mice, whereas ratios in Abcg2 -/- mice remained unchanged. The influence of ABC transporters was completely reversed by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, increasing the brain penetration in wild-type mice by 41-fold while no signs of acute CNS toxicity were observed. Tumor ABCB1 overexpression may thus confer adagrasib resistance. Whereas the ABC transporters did not affect adagrasib plasma exposure, CYP3A and Ces1 strongly impacted its apparent oral availability. The plasma AUC 0–8 h was significantly enhanced by 2.3-fold in Cyp3a -/- compared to wild-type mice, and subsequently 4.3-fold reduced in transgenic CYP3A4 mice, indicating substantial CYP3A-mediated metabolism. Adagrasib plasma exposure was strongly reduced in Ces1 -/- compared to wild-type mice, but tissue exposure was slightly increased, suggesting that adagrasib binds to plasma Ces1c in mice and is perhaps metabolized by Ces1. This binding could complicate interpretation of mouse studies, especially since humans lack circulating CES1 enzyme(s). Our results may be useful to further optimize the clinical safety and efficacy of adagrasib, and give more insight into potential drug-drug interactions risks. [Display omitted] • KRASG12C inhibitor adagrasib is a potent in vivo substrate of ABCB1 and CYP3A. • Adagrasib brain distribution is restricted by ABCB1 and somewhat by ABCG2. • The ABCB1/ABCG2 inhibitor elacridar profoundly enhances adagrasib brain penetration. • CYP3A and carboxylesterase 1 highly influence the oral availability of adagrasib. • Adagrasib likely binds tightly to plasma carboxylesterase 1c in mice. [ABSTRACT FROM AUTHOR]

Purpose: Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel. Methods: Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m on Day 1 of 3-week cycles (5/75 mg/m in Cycles 1 and 2 of Part 3 to allow a safety margin to the cabazitaxel MTD). Patients received repeated oral doses of aprepitant, ketoconazole or rifampin before/during Cycle 2. Cabazitaxel clearance was the primary endpoint; clearance and area under the plasma concentration-time curve (AUC) were normalized to body surface area and dose, respectively. Results: The PK population included 13 (Part 2), 23 (Part 3) and 21 patients (Part 4). Repeated aprepitant administration did not affect cabazitaxel clearance [geometric mean ratio (GMR) 0.98; 90 % confidence interval (CI) 0.80-1.19]. Repeated ketoconazole administration resulted in 20 % decrease in cabazitaxel clearance (GMR 0.80; 90 % CI 0.55-1.15), associated with 25 % increase in AUC (GMR 1.25; 90 % CI 0.86-1.81). Repeated rifampin administration resulted in 21 % increase in cabazitaxel clearance (GMR 1.21; 90 % CI 0.95-1.53), associated with 17 % decrease in AUC (GMR 0.83; 90 % CI 0.65-1.05). The GMR of AUC with rifampin administration was 1.09 (90 % CI 0.9-1.33), suggesting that rifampin had a low impact during the initial phases of cabazitaxel elimination. Safety findings were consistent with previous results. Conclusions: Cabazitaxel pharmacokinetics are modified by drugs strongly affecting CYP3A. Co-administration of cabazitaxel with strong CYP3A inhibitors or inducers should be avoided. [ABSTRACT FROM AUTHOR]

Abstract: Stereoselective differences in pharmacokinetics between clausenamide (CLA) enantiomers have been found after intravenous and oral administration of each enantiomer to rats. The differences could be associated with excretion and first-pass metabolism of two enantiomers. The data from this study demonstrated that (−)CLA was mainly excreted in feces with 13.9% of dose, whereas (+)CLA in bile with 17.2%. A large portion of CLA enantiomers could be transformed into hydroxyl metabolites. In the in vitro metabolic system using rat liver microsomes, it was found that (−)CLA was cleared more than its antipode with peak height ratios [(+)/(−)] from 1.0 to 1.8 at the corresponding substrate concentrations from 0.25 to 2mM. Further study in rabbits showed that two enantiomers underwent an intermediate degree of first-pass metabolism. (−)CLA had lower concentrations and AUC0–8h in the portal vein and heart than those of (+)CLA with rates of hepatic extraction 64.7% for (−)-isomer and 50.8% for (+)-isomer, and intrinsic metabolic clearances of (−) and (+)CLA being 186.3 and 107.2 (l/h), respectively. The first-pass metabolism was involved in CYP3A enzymes in the gut and liver, and different levels of CYP3A1 expression induced by (−)CLA or (+)CLA. Immunohistochemical analyses revealed that (−)-isomer significantly increased the expression of CYP3A1, while (+)-isomer had no obvious effects on it. Taken together, the results provided new evidence that stereoselective pharmacokinetics of CLA enantiomers could be resulted from their stereoselective excretion, first-pass metabolism and induction to metabolizing enzymes, which might be important in understanding the clinic pharmacology of active eutomer, (−)CLA, for treatment of Alzheimer’s disease. [Copyright &y& Elsevier]

ABSTRACT The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P-glycoprotein (P-gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and Cmax of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P-gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P-gp and Cyp3A between the two taxanes. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Danshen (Salvia miltiorrhiza) contains tanshinones, which inhibit P-glycoprotein (P-gp) and the cytochrome P450 (CYP) system. In the present study, we evaluated the possible pharmacokinetic interactions of Danshen extract with docetaxel and clopidogrel in rats. Docetaxel (5mg/kg intravenously and 40mg/kg orally) or clopidogrel (30mg/kg orally) was administered to rats with or without oral co-administration of Danshen (400mg/kg). Co-administration of Danshen did not affect the plasma concentration profiles and pharmacokinetic parameters of docetaxel and clopidogrel, whereas cyclosporine A, a P-gp and CYP3A inhibitor, significantly influenced the pharmacokinetics of co-administered docetaxel and clopidogrel. Orally administered Danshen had no substantial effect on the pharmacokinetics of docetaxel and clopidogrel, suggesting the negligible safety concern of Danshen in P-gp- and CYP3A-mediated interactions in vivo. [Copyright &y& Elsevier]

Abstract: Midazolam is an ultra short acting benzodiazepine derivative and a specific probe for phenotyping cytochrome P450 (P450) 3A4/5 activity. A rapid, sensitive, and selective LC–MS/MS method was developed for simultaneous quantitation of midazolam and its metabolites (1′-hydroxymidazolam and 4-hydroxymidazolam). Deuterated (D5) analog of midazolam was utilized as an internal standard. Sample preparation either from human plasma (100μL) or liver microsomal incubations involved a simple protein precipitation using acetonitrile (900μL) with an average recovery of >90% for all compounds. The chromatographic separation was achieved using Zorbax-SB Phenyl, Rapid Resolution HT (2.1mm×100mm, 3.5μm) and a gradient elution with 10mM ammonium acetate in 10% methanol (A) and acetonitrile (B). The flow rate was 0.25mL/min and total run time was 5.5min. Calibration curves were linear over the concentration range of 0.100–250ng/mL. The lower limit of quantitation (LLOQ) was 0.1ng/mL for all three analytes. The accuracy and precision, estimated at LLOQ and three concentration levels of quality control samples in six replicates, were within 85–115%. In conclusion, a robust, simple and highly sensitive analytical method was developed and validated for the analysis of midazolam and its metabolites. This method is suitable for characterizing the P450 3A4/5 activity in vitro or in human pharmacokinetic studies allowing administration of smaller doses of midazolam. [Copyright &y& Elsevier]

1. Midazolam, a short-acting benzodiazepine, has been considered a probe for estimating hepatic and intestinal cytochrome P450 (CYP) 3A activity in humans. The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of midazolam administered intravenously (i.v.) and orally (p.o.) at relatively low doses to healthy volunteers. 2. The present study was an open-label, single-sequence trial in three phases distinguished by differing doses of midazolam. Plasma concentrations of midazolam and its metabolites, as well as pharmacodynamic parameters, were measured simultaneously after administration of 5, 15 and 30 μg/kg, i.v., midazolam and 15, 50 and 100 μg/kg, p.o., midazolam. 3. The area under the concentration–time curve (AUC) of midazolam was significantly correlated with dose after both i.v. and oral administration (both P < 0.001). The AUC0–6 of midazolam after oral administration was also well correlated with the area under the effect curve for peak saccadic velocity (PSV; P < 0.018), postural sway area (PSA; P < 0.069) and mental sedation as measured on a visual analogue scale (VAS; P < 0.054), but not for critical flicker fusion. 4. The present study has shown that the pharmacokinetics of midazolam at relatively low doses are linear for both intravenous and oral dosing regimens. In addition, PSV, PSA and VAS may be useful for the simultaneous evaluation of the pharmacokinetics and pharmacodynamics of midazolam at subtherapeutic doses. [ABSTRACT FROM AUTHOR]

Thyroid hormones have been shown to reduce the activity and expression of cytochrome P450 (CYP) 3A4 in vitro. The influence of thyroid hormone on drug action via a CYP3A-dependent pathway has not been elucidated in humans. This is the first report showing the effect of thyroid hormone on CYP3A enzyme activity in humans. Ten healthy volunteers participate in this open-label study, in which the pharmacokinetics of midazolam and the urinary ratios of 6 β-hydroxycortisol/free cortisol before and after 2 weeks of oral administration of triiodothyronine were compared. Triiodothyronine administration significantly reduced the area under the concentration-time curve ratios for 1′-hydroxymidazolam/midazolam from 0.36 to 0.25 (P < .05) and urinary ratios of 6 β-hydroxycortisol/ free cortisol from 6.92 to 5.88 (P < .05). These results strongly suggested that thyroid hormone reduced CYP3A activity in human and may influence the pharmacokinetics of concomitant CYP3A substrate drugs. [ABSTRACT FROM AUTHOR]

Abstract: The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A novel series of CYP3A inhibitors was designed around the structural elements of RTV believed to be important to CYP3A inhibition, with general design features being the attachment of groups that mimic the P2–P3 segment of RTV to a soluble core. Several analogs were found to strongly enhance plasma levels of lopinavir (LPV), including 8, which compares favorably with RTV in the same model. Interestingly, an inverse correlation between in vitro inhibition of CYP3A and elevation of LPV was observed. The compounds described in this study may be useful for enhancing the pharmacokinetics of drugs that are metabolized by CYP3A. [Copyright &y& Elsevier]

Sotorasib (Lumakras™) is the first FDA-approved KRASG12C inhibitor for treatment of patients with non-small cell lung cancer (NSCLC) carrying this mutation. Using genetically modified mouse models, we studied the influence of the efflux transporters ABCB1 and ABCG2, the OATP1a/1b uptake transporters, and the CYP3A drug-metabolizing enzyme complex on the plasma pharmacokinetics and tissue distribution of oral sotorasib. In vitro, sotorasib was a potent substrate for human ABCB1 and a modest substrate for mouse Abcg2, but not for human ABCG2. In vivo , the brain-to-plasma ratio of sotorasib (40 mg/kg) was highly increased in Abcb1a/1b -/- (5.9-fold) and Abcb1a/1b;Abcg2 -/- (7.6-fold) compared to wild-type mice, but not in single Abcg2 -/- mice. Upon coadministering elacridar, an ABCB1/ABCG2 inhibitor, sotorasib brain accumulation increased 7.5-fold, approaching the levels observed in Abcb1a/1b-deficient mice. No acute CNS toxicity emerged upon boosting of the sotorasib exposure. In Oatp1a/1b-deficient mice, we observed a 2-fold reduction in liver disposition compared to wild-type mice, although these uptake transporters had no noticeable impact on sotorasib plasma exposure. However, plasma exposure was limited by mouse Cyp3a and human CYP3A4, as the AUC 0–4 h in Cyp3a -/- mice was increased by 2.5-fold compared to wild-type mice, and subsequently strongly decreased (by 3.9-fold) in Cyp3aXAV mice transgenically overexpressing human CYP3A4 in liver and intestine. Collectively, the oral availability of sotorasib was markedly limited by CYP3A and possibly also by ABCB1 and OATP1a/b, whereas its brain accumulation was strongly restricted by ABCB1. The obtained results may help to further optimize the safety and efficacy of sotorasib in clinical use. [Display omitted] • KRASG12C inhibitor sotorasib is a potent in vivo substrate of ABCB1 and CYP3A. • ABCB1 strongly limits brain disposition, potentially protecting brain metastases. • The ABCB1/ABCG2 inhibitor elacridar can boost sotorasib brain penetration. • CYP3A substantially reduces sotorasib oral availability. • Coadministration of ABCB1 and CYP3A modulators should be applied with caution. [ABSTRACT FROM AUTHOR]

Given the prominent role of cytochrome P450 3A (CYP3A) in the metabolism of drugs, it is critical to determine whether new chemical entities will be affected by the inhibition of this enzyme system and result in clinically relevant drug interactions. Ketoconazole interaction studies are frequently performed to determine a given compound's sensitivity to CYP3A metabolism. The present study evaluated whether probing a sensitive substrate (midazolam) with a potent inhibitor (ketoconazole) at earlier time points (days 1 or 2) might be used to reliably gauge the magnitude of a meaningful interaction. The geometric mean ratios (ketoconazole + midazolamday 5/ketoconazole + midazolamday 1 and ketoconazole + midazolamday 5/ketoconazole + midazolamday 2) for midazolam AUC0-8 were 1.36 and 1.06 with corresponding 90% confidence intervals of (1.17, 1.57) and (0.83, 1.23), respectively. These findings suggest that short-term drug-drug interaction studies can predict the magnitude of change in AUC as reliably as studies using longer duration treatments. [ABSTRACT FROM AUTHOR]

Abstract: Nonionic surfactants are commonly used as excipients in pharmaceutical formulation, but recent studies demonstrate that the ingredients affect the pharmacokinetics of the active drugs. However, the mechanisms are largely unknown. Here, we examined the effects of four common nonionic surfactants polysorbate 20, polyoxyl 35 castor oil, polyoxyl 40 stearate and poloxamer 188, on cytochrome P450 3A in vitro and in vivo using midazolam as a probe. We first examined the effects of these surfactants on the 1′-hydroxylation of midazolam in isolated rat liver and intestinal microsomes. All the surfactants tested inhibited midazolam 1′-hydroxylation in a concentration-dependent manner and presented a mixed competitive inhibitory model with decreased V max and increased K m values in vitro. Among the tested nonionic surfactants, polysorbate 20 was the most potent inhibitor of midazolam 1′-hydroxylation with an IC50 of 2.06 and 0.39mgml−1 in the liver and intestinal microsomes, respectively. These surfactants were also tested in vivo as we investigated their effects on the pharmacokinetics of midazolam in rats. These four surfactants displayed different inhibitory patterns in terms of the AUC of midazolam and 1′-hydroxymidazolam. Polysorbate 20 significantly increased both AUC0–4h and AUC0–∞ of midazolam and decreased the AUC0–4h of 1′-hydroxymidazolam to about 40% (p <0.05) in both single- and multiple-treated rats, along with a significant decrease of the metabolic ratio of 1′-hydroxymidazolam/midazolam to 25%. Polyoxyl 35 castor oil, polyoxyl 40 stearate and poloxamer 188 displayed complicated inhibition on the 1′-hydroxylation of midazolam dependent on the administration formula. These results confirmed that effects of these surfactants would have potential inhibitory effects on cytochrome P450 3A and altered midazolam bioavailability. Therefore, caution is needed when selecting nonionic surfactants in drug formulation. [Copyright &y& Elsevier]

Background: Ifosfamide is a chemotherapeutic agent that requires cytochrome P450 3A (CYP3A) for bioactivation and metabolism. To the authors' knowledge, the correlation between dose, pharmacokinetics, CYP3A, and toxicity has not been fully evaluated. A randomized Phase II trial was performed on 22 soft tissue sarcoma patients treated with doxorubicin (60 mg/m(2)/cycle) and either high-dose ifosfamide (12 g/m(2)/cycle) or standard-dose ifosfamide (6 g/m(2)/cycle). The pharmacokinetics of ifosfamide and CYP3A measurements observed are reported.Methods: Pharmacokinetic parameters for ifosfamide, 2-dichloroethylifosfamide (2-DCE), and 3-dichloroethylifosfamide (3-DCE) were collected after the first ifosfamide infusion in 13 patients. Bayesian designed limited pharmacokinetic data were collected from an additional 41 patients. The erythromycin breath test (ERMBT) was performed on 81 patients as an in vivo phenotypic assessment of CYP3A activity.Results: Fourteen-hour (peak) plasma levels of ifosfamide, 2-DCE, and 3-DCE were found to correlate strongly with the respective area under the curve (AUC) 0-24 values (r=0.97, 0.94, and 0.95; P<.0001). Patients who experienced a grade 3-4 absolute neutrophil count (ANC), platelet, or creatinine toxicity (using the National Cancer Institute Common Toxicity Criteria [version 2]) were found to have statistically significantly higher median 14-hour plasma levels of ifosfamide, 2-DCE, and 3-DCE compared with patients with grade 0-2 toxicity. ERMBT was not found to correlate with pharmacokinetic parameters of ifosfamide and metabolites or toxicity.Conclusions: The 14-hour plasma level of ifosfamide, 2-DCE, and 3-DCE is a simple and appropriate substitute for describing the AUC of ifosfamide after 1 day of a 1-hour to 2-hour infusion of drug. Fourteen-hour plasma levels of ifosfamide and metabolites are useful predictors of neutropenia, thrombocytopenia, and creatinine toxicity. ERMBT was not found to accurately correlate with ifosfamide pharmacokinetics or clinical toxicity. [ABSTRACT FROM AUTHOR]