Rate Of Drug Metabolism Research Articles

Metabolic fate of pitavastatin (NK-104), a new inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. Effects on drug-metabolizing systems in rats and humans.

Pitavastatin (CAS 147526-32-7, NK-104) is a new and very potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and has been approved for treatment of hyperlipoproteinaemia. Pitavastatin has been studied for its effects on hepatic microsomal drug metabolism in rats, and the activities of several drug-metabolizing enzymes have been measured. No induction of the drug metabolizing enzymes (aniline hydroxylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase and UDP-glucuronic acid transferase) was found in the pitavastatin group compared to the control after the multiple administrations of pitavastatin at the dosage of 1-10 mg/kg per day for 7 days. Based on several different in vitro approaches, it is concluded that CYP2C9 is the enzyme responsible for the metabolism of pitavastatin and no metabolite is present in renal and intestinal microsomes. The CYP2C9 polymorphism was not involved in the pitavastatin metabolism. No inhibitory effect in CYP-mediated metabolism was detected on the tolbutamide 4-hydroxylation (CYP2C9) and testosterone 6 beta-hydroxylation (CYP3A4) in the presence of pitavastatin. The results suggested that pitavastatin did not affect the drug-metabolizing systems.

Pharmacological and Toxicological Testing of the Enantiomers of two Chiral Fomocaine Alkylmorpholine Derivatives in Comparison to their in vitro Interactions on Drug Metabolism in Rats

Between the stereoisomers of amide-type local anaesthetics differences have been noticed with respect to pharmacokinetics and side effects, but not regarding local anaesthetic capacity. Therefore, only S-(-)-ropivacaine has been introduced into clinical practice and with bupivacaine both the racemate and the S-(-)-enantiomer (levobupivacaine) are available by now. Based on this background, the aim of the present study was to evaluate if there are also dissimilarities to be found both in the toxicity and in the effectiveness of the enantiomers of two newly synthesized chiral fomocaine alkylmorpholine derivatives, OW3 and OW13, with an additional C2-chain in 2- or an additional C3-chain in 3-position at the morpholine ring, respectively. For this purpose, in vitro the interaction capacity with cytochrome P450 (CYP)-mediated monooxygenase and oxidase functions was investigated using rat liver 9000 g supernatants or microsomes. In vivo LD50, paresis of the N. ischiadicus and surface and conduction anaesthesia (cornea, N. ischiadicus) were tested in rats. The enantiomers of both OW3 and OW13 caused a concentration dependent inhibition of all CYP-mediated model reactions investigated. With all model reactions the (-)-enantiomer of OW3 was less effective than the (+)-form, whereas the opposite was the case with OW13. Also toxicity was lower with the (-)-enantiomer of OW3 and with the (+)-form of OW13 than with the respective counterparts. With both derivatives no clear-cut dissimilarities were noticed in the local anaesthetic capacity of the enantiomers. None of the four compounds caused paresis. Thus, similar to amide-type local anaesthetics, also with the enantiomers of chiral fomocaine alkylmorpholine derivatives differences in pharmacokinetic properties and toxicity could be demonstrated.

2050: Ending the odyssey of the great white plague: Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni

The United Nation's Millennium Development Goal of tuberculosis (TB) elimination by 2050 may be a realizable goal by concerting efforts of the numerous stakeholders involved in the development of novel antituberculous therapeutics. Improving pre-clinical models by the research community is one aspect of the drug development pipeline that will continue to require refinement. Better in vitro and animal models are needed to expand the chemical scaffolds of anti-TB agents. These constructs must be designed and utilized in a manner that is also pertinent to the pediatric population by addressing varying age-based drug metabolism rates. Novel technologies that utilize nanomedicine and genomic research may as well have a significant impact on future therapeutics; however, their development must acknowledge the key populations whose underlying disease pathology continues to drive the pandemic – both adults and children with latent TB, HIV/AIDS and diabetes. Challenging the long-standing orthodoxy of applying equivalent TB treatments for standard first line regimens among the adult and pediatric populations must also continue to be a major focus in future drug development strategies. Studies that include pediatric populations will require a greater variety of medication formulations, biomarkers that do not rely on sputum production and diagnostic technologies that are efficacious in paucibacillary disease. Significant programmatic barriers currently exist in key aspects of the described drug development pipeline, but strategic approaches can overcome these roadblocks – including the complex regulatory requirements involving the inclusion of children in drug trials. All such endeavors will require not only more focused research initiatives, but greater institutional support from the pharmaceutical industry, non-governmental organizations and national health sectors.

The BCS, BDDCS, and Regulatory Guidances

The BCS (Biopharmaceutics Classification System), based on aqueous solubility and intestinal permeability, has been widely used since 1995 to predict drug absorption during the course of pharmaceutical development (1). However, as will be discussed subsequently in more detail, when the BCS concepts were initiated, now more than 15 years ago, the term “intestinal permeability” was used interchangeably with both measures of rate and extent of absorption, believing from the data available at that time that permeability/absorption rate and extent are correlated. The BCS has also been utilized by regulatory authorities to determine whether in vivo bioequivalence studies may be waived for drug products in immediate release solid oral dosage forms (2,3). For example, the U.S. FDA currently grants waiver of in vivo bioequivalence studies for BCS Class 1 (highly soluble and highly permeable) drugs that are formulated in rapidly dissolving, immediate release products (2). In 2005, the BDDCS (Biopharmaceutical Drug Disposition Classification System), based on solubility and metabolism, was developed to predict drug disposition and potential drug-drug interactions in the intestine and/or liver (4). In view of the apparent correlation between drug metabolism and intestinal permeability rate, it was further suggested that extensive drug metabolism may provide an alternate (or additional) tool for characterizing high intestinal permeability under BCS (4,5). However, discrepancies between the two systems have been noted over the years. For instance, assignment of a drug class using BDDCS was not in accordance with that using BCS, and vice versa (4–6). In addition, it was found that some highly permeable drugs (as measured by the extent of absorption)

The effect of interferon-α on the expression of cytochrome P450 3A4 in human hepatoma cells

Interferon α (IFNα) is used to treat malignancies and chronic viral infections. It has been found to decrease the rate of drug metabolism by acting on cytochrome P450 enzymes, but no studies have investigated the consequences of IFNα treatment on the CYP3A4 isoform, responsible for the metabolism of a majority of drugs. In this study, we have examined the effect of IFNα on CYP3A4 catalytic activity and expression in human hepatoma cells. We found that IFNα inhibits CYP3A4 activity and rapidly down-regulates the expression of CYP3A4, independent of de novo protein synthesis. Pharmacologic inhibitors and a dominant-negative mutant expression plasmid were used to dissect the molecular pathway required for CYP3A4 suppression, revealing roles for Jak1 and Stat1 and eliminating the involvement of the p38 mitogen-activated and extracellular regulated kinases. Treatment of hepatoma cells with IFNα did not affect the nuclear localization or relative abundance of Sp1 and Sp3 transcription factors, suggesting that the suppression of CYP3A4 by IFNα does not result from inhibitory Sp3 out-competing Sp1. To our knowledge, this is the first report that IFNα down-regulates CYP3A4 expression largely through the JAK-STAT pathway. Since IFNα suppresses CYP3A4 expression, caution is warranted when IFNα is administered in combination with CYP3A4 substrates to avoid the occurrence of adverse drug interactions.

In Vivo Inhibition of CYP3A-Mediated Midazolam Metabolism by Anchusan in Rats

Cytochrome P450 (CYP)-mediated drug interactions caused by Kampo medicine have not been investigated sufficiently. The current study was conducted to reveal the effect of anchusan, a commonly used Kampo formula for gastrointestinal disease, on CYP3A-mediated drug metabolism in rats. The pharmacokinetics of midazolam (MDZ) was investigated after the single or one-week administration of anchusan (500 mg/kg) to evaluate its inhibitory and inducible effect on CYP3A, respectively. MDZ was administrated 16 h after the last anchsan treatment in the multiple dose study, while their intervals were 2 or 16 h in the single dose study. Unexpectedly, the multiple-pretreatment of anchusan increased the AUC of MDZ by 2.4-fold rather than decreasing it, and the CYP3A contents and activities were unchanged in hepatic and intestinal microsomes of these rats. In contrast, no significant inhibitory effects on MDZ metabolism were observed by the single anchusan pretreatment. In vitro study showed that the preincubation of anchusan and some of its component extracts with rat liver microsomes reduced CYP3A activity in a time- and NADPH-dependent manner. These results suggested that anchusan increased the serum MDZ concentration in rats, at least in part, by the time-dependent inhibition of CYP3A.

Traditional Medicine to Modern Pharmacogenomics: Ayurveda Prakriti Type and CYP2C19 Gene Polymorphism Associated with the Metabolic Variability

Traditional Indian medicine—Ayurveda—classifies the human population into three major constituents or Prakriti known as Vata, Pitta and Kapha types. Earlier, we have demonstrated a proof of concept to support genetic basis for Prakriti. The descriptions in Ayurveda indicate that individuals with Pitta Prakriti are fast metabolizers while those of Kapha Prakriti are slow metabolizers. We hypothesized that different Prakriti may have different drug metabolism rates associated with drug metabolizing enzyme (DME) polymorphism. We did CYP2C19 (Phase I DME) genotyping in 132 unrelated healthy subjects of either sex by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. We observed significant association between CYP2C19 genotype and major classes of Prakriti types. The extensive metabolizer (EM) genotype (∗1/∗1, ∗1/∗2, ∗1/∗3) was found to be predominant in Pitta Prakriti (91%). Genotype (∗1/∗3) specific for EM group was present only in Pitta Prakriti. Poor metabolizer (PM) genotype (∗2/∗2, ∗2/∗3, ∗3/∗3) was highest (31%) in Kapha Prakriti when compared with Vata (12%) and Pitta Prakriti (9%). Genotype (∗2/∗3) which is typical for PM group was significant in Kapha Prakriti (odds ratio = 3.5, P = .008). We observed interesting correlations between CYP2C19 genotypes and Prakriti with fast and slow metabolism being one of the major distinguishing and differentiating characteristics. These observations are likely to have significant impact on phenotype-genotype correlation, drug discovery, pharmacogenomics and personalized medicine.

Drug-Drug Interaction Pattern Recognition

Background and Objective: Drug-drug interaction (DDI) is an important aspect of drug development, especially for safety. When a drug is used concomitantly with other drug(s), one of the major concerns is the change of exposures, including the rate and extent of drug absorption, distribution, metabolism and elimination. To address the concerns, a common practice is to measure and report the differences between the exposure in the presence and in the absence of concomitant medication (COMED). The area under the plasma concentration versus time curve (AUC), maximum plasma concentration (Cmax) and time to reach the Cmax (tmax) changes are usually measured in DDI studies. A usual observation is the different extents of changes among AUC, Cmax and tmax, which may raise concerns in certain therapeutic areas or some special agents. The objective of this study was to investigate the variation among changes of AUC, Cmax and tmax in DDI studies, and its pharmacokinetic manifestation. Data Sources: Based on a list of DDI results from the literature, with the assumptions that the primary parameters of a drug of interest were altered during a DDI, two sets of simulated data were generated according to a single oral dose, one-compartment model. The first set including 24 cases with different half-lives and absorption constants (ka) considered the exposure changes upon independent variation of bioavailability (F), clearance (CL), volume of distribution (Vd) and ka up to 50-fold increases or decreases. The second set considered the exposure changes with simultaneous variation of F, CL, Vd, and ka within 5-fold range (increase or decrease) for a case selected from the first set. Study Selection, Data Extraction and Synthesis: Parameter fold changes (defined in a fashion showing fold increase or fold decreases, including CL fold change, F fold change, Vd fold change and ka fold change) and exposure changes (AUC fold change, Cmax fold change, tmax fold change and fold change difference [AUC fold change — Cmax fold change]) were used to generate plots demonstrating various relationships between parameter fold changes and exposure changes. Based on the observations that AUC was influenced by CL and F, Cmax was affected by all four parameters, tmax was mainly determined by CL and ka, F did little for tmax and ka was unrelated to AUC, a chart was created for DDI pattern recognition. Conclusion: An approach, named DDI pattern recognition, is proposed for didactical purposes. It provides a quick initial estimate for interpreting the DDI results based on the exposure changes. This approach entails the following stages: (i) performing a drug interaction study; (ii) calculating the exposure changes in the presence of COMED compared to those in the absence of COMED, and the fold change difference; (iii) selecting the parameter fold changes that may play important roles in a specific DDI, by estimating their possible ranges; and (iv) interpreting the DDI by integrating all the information available, such as the possible mechanism involved. A quicker and better understanding about the processes, which dominate a DDI, has been achieved using this approach by focusing on integration of all information available and mechanistic interpretation.

Drug-drug interaction pattern recognition.

Background and Objective: Drug-drug interaction (DDI) is an important aspect of drug development, especially for safety. When a drug is used concomitantly with other drug(s), one of the major concerns is the change of exposures, including the rate and extent of drug absorption, distribution, metabolism and elimination. To address the concerns, a common practice is to measure and report the differences between the exposure in the presence and in the absence of concomitant medication (COMED). The area under the plasma concentration versus time curve (AUC), maximum plasma concentration (Cmax) and time to reach the Cmax (tmax) changes are usually measured in DDI studies. A usual observation is the different extents of changes among AUC, Cmax and tmax, which may raise concerns in certain therapeutic areas or some special agents. The objective of this study was to investigate the variation among changes of AUC, Cmax and tmax in DDI studies, and its pharmacokinetic manifestation.Data Sources: Based on a list of DDI results from the literature, with the assumptions that the primary parameters of a drug of interest were altered during a DDI, two sets of simulated data were generated according to a single oral dose, one-compartment model. The first set including 24 cases with different half-lives and absorption constants (ka) considered the exposure changes upon independent variation of bioavailability (F), clearance (CL), volume of distribution (Vd) and ka up to 50-fold increases or decreases. The second set considered the exposure changes with simultaneous variation of F, CL, Vd, and ka within 5-fold range (increase or decrease) for a case selected from the first set.Study Selection, Data Extraction and Synthesis: Parameter fold changes (defined in a fashion showing fold increase or fold decreases, including CL fold change, F fold change, Vd fold change and ka fold change) and exposure changes (AUC fold change, Cmax fold change, tmax fold change and fold change difference [AUC fold change — Cmax fold change]) were used to generate plots demonstrating various relationships between parameter fold changes and exposure changes. Based on the observations that AUC was influenced by CL and F, Cmax was affected by all four parameters, tmax was mainly determined by CL and ka, F did little for tmax and ka was unrelated to AUC, a chart was created for DDI pattern recognition.Conclusion: An approach, named DDI pattern recognition, is proposed for didactical purposes. It provides a quick initial estimate for interpreting the DDI results based on the exposure changes. This approach entails the following stages: (i) performing a drug interaction study; (ii) calculating the exposure changes in the presence of COMED compared to those in the absence of COMED, and the fold change difference; (iii) selecting the parameter fold changes that may play important roles in a specific DDI, by estimating their possible ranges; and (iv) interpreting the DDI by integrating all the information available, such as the possible mechanism involved. A quicker and better understanding about the processes, which dominate a DDI, has been achieved using this approach by focusing on integration of all information available and mechanistic interpretation.

Pharmacokinetic comparisons of hydroxysafflower yellow A in normal and blood stasis syndrome rats

Ethnopharmacological relevance Safflower is a popular Traditional Chinese Medicine (TCM) to invigorate the blood and dispel ‘blood stasis’, which arises from poor blood circulation. The differences of pharmacokinetic properties between normal and blood stasis syndrome rats were seldom reported. Aim of the study The present study was conducted to evaluate the pharmacokinetics of hydroxysafflower yellow A (HSYA) following oral administration of hydroxysafflower yellow A and safflower extract with approximately the same dose of HSYA 100 mg/kg in both normal and acute blood stasis rats. Materials and methods The animals were orally administered with HYSA monomer and safflower extract. The blood samples were collected according to the time schedule. The concentrations of HSYA in rat plasma were determined by HPLC. Various pharmacokinetic parameters were estimated from the plasma concentration versus time data using non-compartmental methods. Results It was found that AUC 0– t , C max, Vd and CL of HSYA in both HSYA monomer and safflower extract in acute blood stasis rats were with significant difference ( P < 0.05) comparing with that in normal rats. Conclusions The results indicated that HSYA was with high uptake and eliminated slowly in the animals with blood stasis syndrome, suggesting that the rate and extent of drug metabolism was altered in acute blood stasis animals.

Amnestic effects of sodium oxybate are less than those of triazolam—reply to Drs. Zvosec and Smith

We would like to thank Drs. Zvosec and Smith for their compliments regarding our recent study of the effects of sodium oxybate and triazolam on different types of memory processes. We agree that these topics are important, in need of rigorous study, and have practical clinical implications. We also agree with Drs. Zvosec and Smith that there are potential differences between the number of forensic cases in which a drug can be detected and in which a drug was actually ingested. The difference between these two numbers is likely to be dependent on several factors, such as the dose of drug administered, the rate of drug metabolism, the storage of drug in body tissues, the ease of drug detection, and the availability of specific and sensitive forensic tests for the drug. For these reasons, the difference between the number of cases in which a drug is detected and the number of cases in which a drug is administered is likely to be larger for GHB compared to other drugs. However, even supposing that the detection of GHB is somewhat underestimated, the number of cases in which GHB is detected represents a small fraction of the number of cases in which ethanol is detected; a drug that is also metabolized relatively quickly (ElSohly and Salamone 1999; Slaughter 2000).

Simultaneous analysis of diazepam and its metabolites in rat plasma and brain tissue by HPLC-UV and SPE

Diazepam is frequently used as an adjuvant during antidepressant therapy. Recently, some studies have suggested that the treatment with benzodiazepines could have different efficacy in depressed patients as opposed to non-depressed ones. To clarify the matter, a study is currently underway, regarding the drug metabolism in rats. In order to obtain a more complete and significant set of data, the main diazepam metabolites have also been considered, namely: nordiazepam, temazepam and oxazepam. A feasible and reliable HPLC method has been developed for the simultaneous determination of these compounds in plasma and brain tissue of rats. The method has been applied to “normal” rats and to genetic rat models of depression in order to estimate drug metabolism in different breeds. Analyte separation was achieved on a C8 reversed phase column using an acidic phosphate buffer/acetonitrile mixture as the mobile phase. The detection wavelength was 238 nm. An original sample pre-treatment, based on solid-phase extraction (SPE) was developed in order to eliminate endogenous interference, using only 250 μL of matrix (brain homogenate or plasma) for a complete analysis. The method has been validated with good results in terms of precision, extraction yield, sensitivity, selectivity and accuracy on both matrices and has been successfully applied to samples from some rats subjected to the preliminary study. The obtained data will hopefully contribute to the clarification of possible differences between depressed and non-depressed subjects with respect to benzodiazepine biotransformation.

CYP2D6 Genotype Predicts Antipsychotic Side Effects in Schizophrenia Inpatients: A Retrospective Matched Case-Control Study

Objective: The aim of the present retrospective pilot study was to examine the clinical impact of the cytochrome P450 (CYP) enzyme CYP2D6 poor metabolizer (PM) genotype in patients taking antipsychotic medication. The impaired metabolic capacity of the PM genotype results in higher steady-state plasma concentrations at a given dose, thus increasing the risk of toxic effects from medication. Methods: We identified 18 PM patients with a schizophrenia spectrum diagnosis from a clinical database covering all patients who have been analyzed in an ongoing standardized CYP2D6 screening program. Each PM patient was carefully matched on age, gender and diagnosis with an intermediate metabolizer (IM) and an extensive metabolizer (EM) from the same database to generate 18 triplets. Clinical data, primarily on side effects of treatment, were obtained from medical records by an experienced research and consultant psychiatrist, who was blinded to the results of the genotyping. Results: We found that extrapyramidal syndrome or tardive dyskinesia (EPS/TD) was significantly more frequent among PM patients than among the matched IM and EM control subjects. This finding was further supported by the significantly higher prevalence of noncompliance among the same PM patients. Importantly, this association was not due to differences in the use of CYP2D6-dependent or EPS/TD-causing medication across the 3 matched patient groups. Conclusions: This leads us to conclude that genetically encoded differences in the rate of drug metabolism through CYP2D6 can predict antipsychotic side effects and prompts the question of whether genotyping early in the course of illness to facilitate adjustment of pharmacotherapy will improve treatment outcomes and reduce side effects.

The Importance of Heterogeneous Nuclear Ribonucleoprotein K on Cytochrome P450 2D2 Gene Regulation: Its Binding Is Reduced in Dark Agouti Rats

Cytochrome P450 (P450) 2D2 (CYP2D2) enzyme is known to metabolize the majority of typical substrates of the human CYP2D6 enzyme, which is the most extensively characterized polymorphic drug-metabolizing enzyme. Despite its impact on drug metabolism in rats, the transcriptional regulation of CYP2D2 remains to be elucidated. We clarified the molecular mechanism of CYP2D2 gene expression. The CYP2D2 gene was positively regulated by the poly(C)-binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K) through a transcriptional regulatory element located in the 5'-flanking region from -94 to -113. To date, nothing is known about the potential role of hnRNP K in P450 gene regulation. Thus, this is the first report that hnRNP K protein is involved in CYP2D2 gene regulation. Furthermore, we elucidated the genetic basis of the extremely low expression of CYP2D2 mRNA in Dark Agouti (DA) rats. Because of its relatively low abundance, DA rats have been frequently used for the study of CYP2D substrate metabolism as the animal model of the poor metabolizer phenotype for CYP2D6 compared with Sprague-Dawley rats as an extensive metabolizer phenotype. We found a single substitution within the transcriptional regulatory element of the CYP2D2 gene in DA rats. The mutation was detected in the polypyrimidine sequence that is the preferred binding site for hnRNP K protein. The mutation within the transcriptional regulatory element attenuated the binding of hnRNP K protein. In conclusion, decreased recruitment of hnRNP K protein to the mutated sequence causes the low expression of CYP2D2 mRNA in DA rats.

Defining the in Vivo Role for Cytochrome b5 in Cytochrome P450 Function through the Conditional Hepatic Deletion of Microsomal Cytochrome b5

In vitro, cytochrome b5 modulates the rate of cytochrome P450-dependent mono-oxygenation reactions. However, the role of this enzyme in determining drug pharmacokinetics in vivo and the consequential effects on drug absorption distribution, metabolism, excretion, and toxicity are unclear. In order to resolve this issue, we have carried out the conditional deletion of microsomal cytochrome b5 in the liver to create the hepatic microsomal cytochrome b5 null mouse. These mice develop and breed normally and have no overt phenotype. In vitro studies using a range of substrates for different P450 enzymes showed that in hepatic microsomal cytochrome b5 null NADH-mediated metabolism was essentially abolished for most substrates, and the NADPH-dependent metabolism of many substrates was reduced by 50–90%. This reduction in metabolism was also reflected in the in vivo elimination profiles of several drugs, including midazolam, metoprolol, and tolbutamide. In the case of chlorzoxazone, elimination was essentially unchanged. For some drugs, the pharmacokinetics were also markedly altered; for example, when administered orally, the maximum plasma concentration for midazolam was increased by 2.5-fold, and the clearance decreased by 3.6-fold in hepatic microsomal cytochrome b5 null mice. These data indicate that microsomal cytochrome b5 can play a major role in the in vivo metabolism of certain drugs and chemicals but in a P450- and substrate-dependent manner.

Stephen Edward Smith

Stephen Edward Smith

Depression Care for Black Women May Hinge on Cultural Factors

Depression Care for Black Women May Hinge on Cultural Factors

Genetic Variation in Drug Transporters in Ethnic Populations

Drug-metabolizing enzymes and membrane transporters work in concert to play crucial roles in drug absorption, distribution, and elimination. It is well recognized that genetic variation in drug-metabolizing enzymes contributes substantially to interindividual differences in drug response. With the notable exceptions of CYP1A1 and CYP2E1, genes encoding cytochrome P450s, which are involved in the metabolism of >80% of all drugs used in clinical practice, are highly polymorphic.1 Interethnic variation in the distribution and frequency of occurrence of variant alleles in drug-metabolizing enzymes is known to alter the rate of drug metabolism in vivo, resulting in interethnic variation in drug disposition and response. Clinical Pharmacology & Therapeutics (2008); 84, 3, 412–416 doi:10.1038/clpt.2008.98

Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism

Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype-genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6alpha-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c.521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0-infinity). Functional studies suggested -271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.

Impact of physiological, physicochemical and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans

The onset, intensity and duration of therapeutic response to a compound depend on the intrinsic pharmacological activity of the drug and pharmacokinetic factors related to its absorption, distribution, metabolism and elimination that are inherent to the biological system. The process of drug transfer from the site of administration to the systemic circulation and the interspecies factors that impact this process are the scope of this review. In general, the factors that influence oral drug bioavailability via absorption and metabolism can be divided into physicochemical/biopharmaceutical and physiological factors. Physicochemical and biopharmaceutical factors that influence permeability and solubility tend to be species independent. Although there are significant differences in the anatomy and physiology of the gastrointestinal tract, these are not associated with significant differences in the rate and extent of drug absorption between rats and humans. However, species differences in drug metabolism in rats and humans did result in significant species differences in bioavailability. Overall, this review provides a better understanding of the interplay between drug physicochemical/biopharmaceutical factors and species differences/similarities in the absorption and metabolism mechanisms that affect oral bioavailability in rats and humans. This will enable a more rational approach to perform projection of oral bioavailability in human using available rat in vivo data.