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Small phytochemicals play an important role in therapeutics hence potential molecules in different spices are screened using Lipinski's and Veber's rule. Pharmacodynamics studies are carried out against the cancer target, DNA topoisomerase III alpha. In silico ADMET (absorption, distribution, metabolism, excretion, toxicity) studies are done with these compounds. Lipinski's and Veber's rule indicates that all 10 small phytochemicals have the potential to behave as oral drug‐like molecules. A molecular docking study shows that shogoal, demethoxycurcumin, capsaicin, ellagic acid, 6‐paradol, 6‐gingerol, carnosic acid, and curcumin bind strongly with the cancer target: human DNA topoisomerase‐III alpha. In silico absorption, a study reveals that only cinnamic acid, allicin, alpha turmerone, cinnamyl acetate, and carnosic acid have more than 96% human intestinal absorption, but only alpha turmerone can cross both the blood–brain barrier and central nervous system. In silico phase‐I, the metabolism study shows 6‐paradol and carnosic acid as substrates for cytochrome 450 enzyme (CYP450 3A4) and curcumin and dillapiol as inhibitors for CYP 450 2D6. Overall the study concludes that small phytochemicals present in different spices have the potential to be proposed as oral anti‐cancer drugs against cancer targets DNA topoisomerase III alpha. [ABSTRACT FROM AUTHOR]

Abstract Background Clopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China. Methods One hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected. Results The frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77–25.04; p = 0.005); 22.74(95% CI, 3.11–166.27; p = 0.002); 5.69 (95% CI,1.06–30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*1/*2, *1/*3, *2/*2, *2/*3 was significantly higher than no mutant genotype (18/40vs.2/63,3/9vs.2/63, 11/6vs.2/63, 7/1vs2/63, respectively). There was no significant correlation between PON-1Q192R mutant allele and MACE. Conclusion Our study was first time to report on CYP2C19 and PON-1 polymorphisms in Jin Hua population in the middle of Zhe Jiang province in China. The carriage of CYP2C19*2 or *3 mutant allele significantly reduced the platelet response to clopidogrel and increase the MACE. The carriage of PON-1 mutant allele also significantly reduced the platelet response to clopidogrel, but would not increase the major adverse cardiac events after 1 year follow-up. Trial registration ChiCTR, ChiCTR1800018316. Registered 11 September 2018 – prospective registered, http://www.chictr.org.cn/edit.aspx?pid=30927&htm=4.

Couple of ethnopharmacological surveys in the Indian Ladakh and Pakistani Shigar valleys has reported the medicinal use of Acantholimon lycopodioides against cardiac and gastric disorders that however, remains without scientific rationale or experimental validations. Here, we assess the in vitro bio/therapeutic activities of A. lycopodioides extracts as well as chloroform, ethyl acetate, n-butanol and aqueous fractions. The in vitro β-carotene-linoleic acid bleaching and DPPH radical scavenging methods demonstrated a very high anti-oxidative property of chloroform and ethyl acetate fractions compared to others. Cell viability assay (MTT) on human cervical (HeLa), breast (MDA-MB321) and liver (HepG2) cancer cells revealed their differential cytotoxicity, except the chloroform fraction. Of these, the precipitate exerted highest cytotoxicity on HepG2 cells followed by aqueous fraction on MDA-MB321 cells. Notably, the non-cytotoxicity of chloroform fraction coincided with its highest anti-oxidative activity. Further, the chloroform fraction showed marked hepatoprotection (up to 84%) against 3′7′dichlorofluorescin triggered free radicals induced oxidative damage. Also, the hepatoprotective chloroform fraction mildly activated CYP3A4 in HepG2 cells (dual-luciferase assay). Moreover, the A. lycopodioides extracts and fractions showed differential anti-bacterial and anti-fungal activities. Of these, while S. aureus was more sensitive to the water-insoluble extract, ethyl acetate fraction showed moderate activity against E. coli and C. albicans. On the other hand, the chloroform fraction showed promising activity against S. Aureus , C. albicans, P. vulgaris and E. faecalis. In conclusion, our data for the first time, demonstrated promising anti-oxidative, hepatoprotective, anti-cancer, anti-microbial and CYP3A4 activating salutations of A. lycopodioides. This warrants further studies towards isolation and identification of its therapeutically active principles. [ABSTRACT FROM AUTHOR]

Background: Clopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China. Methods: One hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected. Results: The frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77–25.04; p = 0.005); 22.74(95% CI, 3.11–166.27; p = 0.002); 5.69 (95% CI,1.06–30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*1/*2, *1/*3, *2/*2, *2/*3 was significantly higher than no mutant genotype (18/40vs.2/63,3/9vs.2/63, 11/6vs.2/63, 7/1vs2/63, respectively). There was no significant correlation between PON-1Q192R mutant allele and MACE. Conclusion: Our study was first time to report on CYP2C19 and PON-1 polymorphisms in Jin Hua population in the middle of Zhe Jiang province in China. The carriage of CYP2C19*2 or *3 mutant allele significantly reduced the platelet response to clopidogrel and increase the MACE. The carriage of PON-1 mutant allele also significantly reduced the platelet response to clopidogrel, but would not increase the major adverse cardiac events after 1 year follow-up. Trial registration: ChiCTR, ChiCTR1800018316. Registered 11 September 2018 – prospective registered, http://www.chictr.org.cn/edit.aspx?pid=30927&htm=4. [ABSTRACT FROM AUTHOR]

Citrinin (CIT) is one of by-products by Monascus fermentation with known nephrotoxicity. Except dihydro-citrinone, no other metabolites including the possible metabolic pathways have been found in vivo metabolism. In this study, we applied ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to analyze and identify potential CIT metabolites in the human cytochrome 450 (P450) subtype system. Four new metabolites with liver microsomes incubation were first found, namely 3-hydroxy-citrinin (M1), 4,5-ene-citrinin (M2), 5-hydroxymethyl-citrinin (M3), and 7-hydroxy-citrinin (M4). We also found the distinguished levels of the four metabolites with the incubation of various P450 subtypes. According to the results of molecular docking prediction, it showed the metabolic correlation of CYP3A4 with M1, CYP1A2, CYP2C9, and CYP2D6 with M2, M3, and M4. The maximum level of M1 metabolite was found in the incubation with liver microsome and P450 subtypes. Moreover, M1 and M4 metabolites were found in mice's duodenum, jejunum, ileum, liver, kidney, and hippocampus, but not M2 and M3. These results indicated the mediation of citrinin metabolism by P450s. It also suggested the concentration differences of metabolites with the incubation of different P450 subtypes. [Display omitted] • First found four new citrinin metabolites with incubation of liver microsome. • Found the metabolic pathway of citrinin with P450 mediation. • Found citrinin and metabolites M1 and M4 in in vivo metabolic systems. [ABSTRACT FROM AUTHOR]

The hepatic cytochrome P450 (CYP450) enzyme superfamily is one of the most important drug-metabolizing enzyme systems, which is responsible for the metabolism of a large number of clinically relevant medications used in traumatic brain injury (TBI) therapy. Modification of CYP450 expression may have important influences on drug metabolism and lead to untoward effects on those with narrow therapeutic windows. However, the impact of blast-induced TBI (bTBI) on the expression of CYP450 has received little attention. The subfamilies of CYP1A, 2B, 2D, and 3A account for about 85 % of all human drug metabolism of clinical significance. Therefore, in this study, we investigated the expressions of hepatic CYP1A2, CYP2B1, CYP2D1, and CYP3A2 in rats suffering bTBI. Meanwhile, we also measured some important cytokines in serum after injury, and calculated the correlation between these cytokines and the expressions of CYP1A2, CYP2B1, CYP2D1, and CYP3A2. The results showed that bTBI could significantly reduce mRNA expressions of CYP1A2, CYP2D1, and CYP3A2 at the early stage and induce the expressions from 48 h to 1 week after injury. The protein expressions of these CYP450s had all been downregulated from 24 to 48 h post- injury, and then began to elevate at 48 h after bTBI. The cytokines, IL-1β, IL-2, IL-6, and TNF-α, increased significantly in the early phase, and began to reduce at the delayed phase of bTBI. The serum levels of IL-1β, IL-6, and TNF-α but not IL-2 were significantly negative correlated with the mRNA expressions of CYP2B1 and CYP2D1 and the proteins expressions of CYP1A2, CYP2B1, CYP2D1, and CYP3A2. In conclusion, our work has, for the first time, indicated that bTBI has significant impact on the expressions of CYP1A2, CYP2B1, CYP2D1, and CYP3A2, which may be related to the cytokines induced by the injury. [ABSTRACT FROM AUTHOR]

The rapid increase in demand and development of industrial chemicals, to sustain and improve quality of life worldwide have resulted in the contamination and high prevalence of chemicals into environment, posing a potential threat to the biota. Hence all organisms are exposed constantly and unavoidably to these foreign chemicals, or xenobiotics, which include both manufactured and natural chemicals such as drugs, industrial chemicals, pesticides, pollutants, pyrolysis products, alkaloids, secondary plant metabolites, and toxins produced by molds, plants, and animals. The toxicity or the contamination of chemicals can be reduced by viable bioremediation solution with many intermediate or degradation products. In this remedial process, cytochromes P450 (CYPs) are key enzymes in the metabolization of all xenobiotics by catalyzing oxidations of the substrate and are polymorphic in nature. Cytochrome P450 genes constitute one of the largest gene superfamilies, with representatives in all living organisms, including bacteria, fungi, insects, plants, and animals. The catalytic versatility and substrate diversity of CYP enzymes have led to considerable interest in utilizing them as biocatalysts for many biotechnological applications (such as synthesis of drugs chemicals, metabolization of endogenous compounds, such as fatty acids and vitamins to maintain homeostasis, targeted gene therapy, cancer treatment) other thanbioremediation. In this review we primarily discuss 1) background information about CYPs including its occurrence, classification and mechanism 2) the role of CYP enzymes in bioremediation for detoxification of industrial and environmental pollutants special reference to "Morpholine" and 3) engineered CYPs enzymes and their potential role in transgenic plant-mediated phytoremediation. [ABSTRACT FROM AUTHOR]

This study aimed to assess cytochrome ( CY) P450-2D6*4 polymorphism relationship with semen variables in infertile men. In all, 308 men were included; fertile normozoospermia (N) ( n = 77), asthenozoospermia (A) ( n = 70), asthenoteratozoospermia ( AT) ( n = 75) and oligoasthenoteratozoospermia ( OAT) ( n = 86). They were subjected to history taking, clinical examination, semen analysis, sperm acrosin activity, seminal malondialdehyde ( MDA) and CYP450-2D6*4 genotyping. CYP450-2D6*4 wild-type allele was represented in 76.5% of N, 70% of A, 66.7% of AT and 57.7% of OAT men where homozygous gene mutation was present in 5.9% of N, 20% of A, 26.6% of AT and 26.9% of OAT men, respectively. Sperm acrosin activity, sperm concentration, sperm motility, linear sperm velocity and sperm normal forms were significantly higher, and seminal MDA level was significantly lower in men with CYP450-2D6*4 wild-type allele compared with men with homozygous mutation. It is concluded that CYP450-2D6*4 wild-type allele has higher frequency where homozygous-type allele has lower frequency in N men compared with A, AT and OAT men. Sperm acrosin activity index, sperm concentration, sperm motility, linear sperm velocity and sperm normal forms were significantly higher, and seminal MDA level was significantly lower in men with CYP450-2D6*4 wild-type allele compared with men with homozygous mutation. [ABSTRACT FROM AUTHOR]

It was predicted that the genome of silkworm, Bombyx mori, has at least 79 P450 genes; however, P450 genes that are related to the catabolism of exogenous compounds were not reported. In this study we cloned two CYP4 (named CPY4M5 and CYP4M9) and four CYP6 (named CYP6AB5, CYP6AE9, CYP6AE22 and CYP6AU1) genes by using both bioinformatics and RT-PCR approaches. Sequence analysis showed that these genes contained conserved P450 gene sequence regions and one conserved intron. CYP4M5 and CYP4M9 genes were clustered together in a mode of 'head-to-tail' possibly due to gene duplication. Blast analysis showed that these P450 genes shared significant similarity with CYP4 and CYP6 genes that are involved in the catabolism and detoxification of exogenous compounds in other insect species. RT-PCR results showed that these P450 genes were highly expressed in the midgut and fat body of B. mori. As the instar age increased, these P450 genes exhibit different expression patterns. When B. mori was exposed to 1.75 × 10% of cypermethrin, 3.5 × 10% of cypermethrin and 0.1 % of rutin, expression of CYP6AB5 was increased by 2.3-fold, 2.2-fold and 1.9-fold, respectively. Exposure of B. mori to 0.1 % quercetin does not change the expression of CYP6AB5. In contrast, expression of the other five P450 genes was inhibited after exposed to these compounds. [ABSTRACT FROM AUTHOR]

Abstract: Primary cultures of rat hepatocytes were used to investigate whether and how eight isothiocynates (ITCs) with different chemical structures (the aromatic benzyl, 4-hydroxybenzyl, phenethyl isothiocyanates and the aliphatic allyl, napin, iberin, raphasatin isothiocyanates and sulforaphane) derived from hydrolyzed glucosinolates, were able to modulate cytochrome P450 (CYP) and antioxidant/detoxifying enzymes and to activate the Nrf2 transcription factor. The aromatic ITCs at 40μM markedly increased the transcription of CYP1A1 and 1A2 mRNA and increased the associated ethoxyresorufin O-deethylase (EROD) activity after 24h of treatment. By contrast, the aliphatic ITCs (40μM) decreased CYP1A1 and 1A2 transcription, together with the corresponding EROD activity. The same treatment also caused a striking and similar transcriptional repression of CYP3A2, and the corresponding benzyloxyquinoline debenzylase activity in response to all the ITCs tested. In the same culture conditions, most of the antioxidant/detoxifying enzymes were significantly up-regulated by 40μM ITCs. In particular, NAD(P)H:quinone oxidoreductase and heme oxygenase-1 were induced, although to different levels, at transcriptional, protein and/or activity levels by all the ITCs. However, glutathione S-transferase activity was not induced by the allyl, benzyl, and 4-hydroxybenzyl ITCs, glutathione reductase activity was not induced by benzyl, and 4-hydroxybenzyl ITCs and catalase activity was not induced by allyl ITC. As for the Nrf2 transcription factor, a partial translocation of its protein from the cytosol to the nucleus was revealed by immunoblotting after 1h of treatment for all the ITCs tested. The ability of ITCs to induce the antioxidant and phase II enzymes did not appear to be affected by their hydrophilicity or other structural factors. Taken together, these results show that these ITCs are effective inducers of ARE/Nrf2-regulated antioxidant/detoxifying genes and have the potential to inhibit, at least in rat liver, the bioactivation of carcinogens dependent on CYP3A2 catalysis. [Copyright &y& Elsevier]

Abstract: It has been reported that malaria reduces cytochrome-P450 (CYP) content and monooxygenase activities in the mammalian host liver. The mechanism by which malaria modulates CYP activities, however, remains unclear. In this study we found that activities of ethoxy- and benzyloxy-resorufin-O-dealkylases, p-nitrophenol-hydroxylase and erythromycin-N-demethylase (mediated by CYP1A, 2B, 2E1 and 3A, respectively) were depressed, while uridine-glucuronosyl-transferase (a phase 2 enzyme) was unaltered in liver microsomes of Plasmodium berghei-infected (parasitemia >20%) male Swiss Webster mice. Prolongation of midazolam sleeping time and a slower clearance of chlorzoxazone were also noted in infected mice. Reductions of hepatic levels of CYP1A2, 2E1 and 3A11 mRNAs indicated that malaria downregulated these CYP-mediated activities at a pre-translational level. [Copyright &y& Elsevier]

Abstract: Previous studies in rainbow trout have shown that acclimation to hypersaline environments enhances the toxicity to thioether organophosphate and carbamate pesticides. In order to determine the role of biotransformation in this process, the metabolism of the thioether organophosphate biocide, fenthion was evaluated in microsomes from gills, liver and olfactory tissues in rainbow trout (Oncorhynchus mykiss) acclimated to freshwater and 17‰ salinity. Hypersalinity acclimation increased the formation of fenoxon and fenoxon sulfoxide from fenthion in liver microsomes from rainbow trout, but not in gills or in olfactory tissues. NADPH-dependent and independent hydrolysis was observed in all tissues, but only NADPH-dependent fenthion cleavage was differentially modulated by hypersalinity in liver (inhibited) and gills (induced). Enantiomers of fenthion sulfoxide (65% and 35% R- and S-fenthion sulfoxide, respectively) were formed in liver and gills. The predominant pathway of fenthion activation in freshwater appears to be initiated through initial formation of fenoxon which may be subsequently converted to the most toxic metabolite fenoxon R-sulfoxide. However, in hypersaline conditions both fenoxon and fenthion sulfoxide formation may precede fenoxon sulfoxide formation. Stereochemical evaluation of sulfoxide formation, cytochrome P450 inhibition studies with ketoconazole and immunoblots indicated that CYP3A27 was primarily involved in the enhancement of fenthion activation in hypersaline-acclimated fish with limited contribution of FMO to initial sulfoxidation. [Copyright &y& Elsevier]

Interference of antiviral agent adefovir, i.e. 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with microsomal drug metabolizing system was investigated in rats. The content of total liver cytochrome P450 (CYP) was lowered while that of its denaturated form, P420, was elevated in animals intraperitoneally treated with PMEA (25 mg/kg). Similar effect was observed after treatment with a prodrug of adevofir, adefovir dipivoxil (bisPOM-PMEA). The CYP2E1-dependent formation of 4-nitrocatechol from p-nitrophenol was diminished, though the specific activity of p-nitrophenol hydroxylase remained unchanged. PMEA had no influence on expression of CYP2E1 protein and mRNA and mRNAs of other P450 isoenzymes (1A1, 1A2, 2C11, 3A1, 3A2, and 4A1). It may be concluded that repeated systemic administration of higher doses of PMEA results in a partial degradation of rat CYP protein to inactive P420. [ABSTRACT FROM AUTHOR]

Cytochrome P-450 dependent oxygenase (3′-hydroxy-hexobarbital) and oxidase activities (hydrogen peroxide) have been measured in hepatic microsomes from guinea pigs, rats and rabbits. A sensitive gas-chromatographic assay was developed to measure the hydroxylated product 3′-hydroxy-hexobarbital. The kinetics of its formation were determined and correlated to hexobarbital type I binding and compared with oxidase activity: in the rat, V for 3′-hydroxy-hexobarbital formation and for hexobarbital-dependent HO formation was 5.1 and 2.6 nmoles/mg/min, resp. This was increased by phenobarbital tratment to 15.2 and 13.4 nmoles/mg/min. In phenobarbital treated rabbits, V was 15.0 nmoles/mg/min for hydroxylation and 40.8 for HO formation. Spectral affinity constants ( K) in control animals were 0.12 mM (rats) and 0.14 mM (rabbits). Phenobarbital treatment decreased these affinity constants, which were similar for each activity measured. In guinea pigs, however, hydroxylation of hexobarbital was low (3.1 nmoles/mg/min) and hexobarbital-dependent formation of HO was higher than hydroxylation ( V:7.0 nmoles/mg/min). Phenobarbital treatment led here to two affinity constants for each activity measured, which however, were alike. The existence of low in addition to high affinity constants observed here might explain the difficulties seen hitherto in correlating hexobarbital binding and metabolism in this species. Total oxidase activity was higher than oxygenase activity in all species tested. It is suggested that oxygenase activity of cytochrome P-450 is not limited by binding but by a competition with oxidase activity for a common intermediary species. This might be peroxy-P-450 (substrate-FeO), rendering either substrate-FeO for hydroxylation reaction, or oxidized cytochrome P-450-substrate and hydrogen peroxide as product of oxidase function. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) drug-to-drug interactions are underrecognized by clinicians. Apixaban has cytochrome 450 (CYP) mediated metabolism (primarily by CYP3A4). Strong inducers and inhibitors of this enzyme may cause variations in the blood level of apixaban. This report presents a patient who received a femoral artery stent and developed a large retroperitoneal hemorrhage after she was prescribed apixaban in addition to her antiretroviral therapy (AVT) regimen that included cobicistat, a strong CYP3A4 inhibitor. The patient was managed conservatively, and a repeat computed tomography scan in a subsequent admission revealed near resolution of the hematoma. The treating physicians realized that apixaban should not be prescribed with a potent CYP3A4 inhibitor like cobicistat and discontinued it., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ammar et al.)

The spatial distributions of cytochrome P450 (CYP450) and glutathione (GSH) in liver lobules determine the heterogeneous hepatotoxicity of acetaminophen (APAP). Their interplay in conjunction with blood flow is not well understood. In this paper, we integrate a cellular APAP metabolism model with a sinusoidal blood flow to simulate the temporal‐spatial patterns of APAP‐induced hepatotoxicity. The heterogeneous distribution of CYP450 and GSH is modeled by linearly varying their reaction rates along the portal triad to the central vein axis of a sinusoid. We found that the spatial distribution of GSH, glutathione S‐transferases (GSTs), and CYP450 all contributes to the high acetaminophen protein adduct formation at zone 3 of the lobules. The reversed spatial gradients of CYP450 and GSH cause quick depletion of GSH, which is further accelerated by the distribution of GST. The hepatic flow congestion and hyperperfusion however do not seem to play a significant role in the zonal hepatotoxicity. The simulation results may be useful for understanding the APAP‐induced hepatotoxicity and associated pharmaceutical treatment. [ABSTRACT FROM AUTHOR]

Background: Metoclopramide is metabolized by various cytochrome P450 (CYP) enzymes such as CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Rifampicin is a non-selective inducer of P-glycoprotein (P-gp) and CYP enzymes such as CYP3A4 and others., Objective: This study was aimed at the evaluation of rifampicin's enzyme induction effect on the pharmacokinetic parameters of orally administered metoclopramide., Method: This randomized, single-blind, two-phase cross-over pharmacokinetic study separated by a 4-week washout period was conducted at a single center in Pakistan. It involved twelve Pakistani healthy male volunteers (nonsmokers) divided into two groups. In the reference phase, each volunteer received a single oral dose of 20 mg metoclopramide (Maxolon 10 mg, GlaxoSmithKline, Pakistan), while in the rifampicin-treated phase, each volunteer received 600 mg rifampicin once daily for 6 days through oral route. On day 6, metoclopramide (20 mg) was administered 2 hours after the last pretreatment dose of rifampicin. The serial blood samples were collected on predetermined time points (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 18 h) and analyzed using a validated HPLC method for the determination of pharmacokinetic parameters, i.e. Cmax, Tmax, and AUC0-∞ of metoclopramide. The whole study was monitored by an unblinded clinician for the purpose of volunteer's health safety., Results: All the volunteers participated in the study until the end. Twelve healthy Pakistani males having mean age 26.0 (range 20.6-34.1) years and body mass index 25.1 (range 16.2-31.5) kg/m2 were included in this study after taking written informed consent. Rifampicin significantly (P<0.05) decreased the mean Cmax, AUC0-∞ and T1/2 of metoclopramide by 35%, 68%, and 44%, respectively. The laboratory tests did not reveal any significant change in the biochemical, physical, hematological, or urinalytical values before and after metoclopramide treatment. None of the volunteers complained of any discomfort during the study., Conclusion: Rifampicin noticeably decreased the concentration of plasma metoclopramide. These results give in vivo confirmation of the CYP3A4 involvement in the metoclopramide metabolism, in addition to CYP2D6. Therefore, metoclopramide pharmacokinetics may be clinically affected by rifampicin and other potent enzyme inducers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Objectives: Statins are safe but have a significant potential for pharmacological interactions. The objective of the study was to evaluate the prevalence of potential interactions throughout the cytochrome P450 isoenzyme 3A4 (CYP3A4) system in a large sample of statin-treated subjects and to determine which factors, from the patient and the physician, were associated with a higher risk of interactions., Patients and Methods: This is an observational, cross-over, population study that included 7,880 subjects treated with statins. Both data from patients and from the1,681 participating physicians were recorded and analyzed., Results: Fifty-nine percent of the participants were receiving a statin metabolized by the CYP3A4, and 21.5% of all participants received a drug, different from a statin, metabolized by the CYP3A4. There were no differences in the frequency of utilization of statins metabolized or not by the CYP3A4 in relation to the simultaneous prescription of drugs metabolized by the same pathway (22 vs. 21%, respectively). Globally, 12.9% of all participants were at risk of an interaction. These patients were older, received a higher number of drugs and had more comorbidity. Sixty percent of the physicians mentioned that the possibility of an interaction greatly conditioned their selection of a particular statin. Likewise, 56% of them had software that alerted of possible interactions. These aspects, however, did not influence the number of patients at risk of interactions., Conclusion: The proportion of statin-treated patients at risk of interaction is elevated. Physicians do not usually pay attention to this possibility despite having available alert software and therapeutic alternatives., (Copyright © 2013 Elsevier España, S.L.U. All rights reserved.)