Relevance of induction of human drug‐metabolizing enzymes: pharmacological and toxicological implications

Park, B. K.; Kitteringham, Neil R.; Pirmohamed, Munir; Tucker, Geoffrey T.

doi:10.1046/j.1365-2125.1996.03482.x

Cited by 94 publications

(48 citation statements)

References 39 publications

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“…In addition to drugs, ethanol, cigarette smoking, and herbal products such as St. John's Wort are also capable of inducing certain P450 enzymes. Several review articles have been published that detail the biochemical mechanisms involved in P450 induction and the clinical importance of P450 induction (Bresnick et al, 1984;Park et al, 1996;Ma and Lu, 2007).…”

mentioning

confidence: 99%

In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective

Chu¹,

Einolf²,

Evers³

et al. 2009

Drug Metab Dispos

153

122

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ABSTRACT:Cytochrome P450 (P450) induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drug-drug interactions due to P450 induction. There is a desire from the pharmaceutical industry and regulatory agencies to harmonize assay methodologies, data interpretation, and the design of clinical drug-drug interaction studies. In this article, a team of 10 scientists from nine Pharmaceutical Research and Manufacturers of America (PhRMA) member companies conducted an anonymous survey among PhRMA companies to query current practices with regards to the conduct of in vitro induction assays, data interpretation, and clinical induction study practices. The results of the survey are presented in this article, along with reviews of current methodologies of in vitro assays and in vivo studies, including modeling efforts in this area. A consensus recommendation regarding common practices for the conduct of P450 induction studies is included.The convergence of recent advances in molecular biology and genomics, higher throughput chemical synthesis, and automated highthroughput in vitro enzyme and cell-based assays to assess biological activity has led to shorter lead identification and optimization times in drug research. However, these breakthroughs have not yet translated into success in drug development. Surveys suggest that in the last several years, the number of New Drug Applications submitted to regulatory agencies has declined and that the poor success rate during drug development is to some extent due to late-stage failures. It is important that novel and innovative approaches are used for assessing the risks and benefits of new molecular entities (NMEs) early in the research and development life cycle to minimize late-stage attrition.Based on a survey conducted in 2004, the major factors for compound attrition during clinical development are lack of efficacy, toxicity, and safety, and suboptimal pharmacokinetics and/or bioavailability, with the remaining failures due to financial and/or commercial reasons (Kola and Landis, 2004). In that survey, one notable observation was the reduction of compound attrition due to pharmacokinetic and/or bioavailability issues from pre-1991 to the period be- ABBREVIATIONS: NME, new molecular entity; P450, cytochrome P450; DDI, drug-drug interaction; RIF, rifampicin; PhRMA, Pharmaceutical Research and Manufacturers of America; AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; UGT, uridine diphosphate glucuronosyl transferase; FXR, farnesyl X receptor; PPAR, peroxisome proliferator-activated receptor; VDR, vitamin D receptor; Nrf2, nuclear factor erythroid 2-related factor 2; LBD, ligand binding domain; hPXR, human PXR; SR12813, tetra-ethyl 2-(3,5-di-tertbutyl...

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mentioning

confidence: 99%

In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective

Chu¹,

Einolf²,

Evers³

et al. 2009

Drug Metab Dispos

153

122

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“…Therefore, these enzymes are involved in many pharmacokinetic drug-drug interactions (DDIs), where multiple drug therapy results in the interference of one drug with the metabolism of another (Guengerich, 1997). Drug interactions mediated by P450 induction is a well established mechanism of pharmacokinetic DDIs and can result either in a marked increase in production of a toxic metabolite (Lin and Lu, 1998) or can reduce the efficacy of other coadministered medications because of an increase in clearance (Park et al, 1996). A more comprehensive listing of drugs that are inducers of P450 enzymes can be found in Dave Flockhart's P450 drug interaction tables (http://medicine.iupui.edu/flockhart/) and is reported by Michalets (1998).…”

mentioning

confidence: 99%

Cytochrome P450 Gene Induction in Rats Ex Vivo Assessed by Quantitative Real-Time Reverse Transcriptase-Polymerase Chain Reaction (Taqman)

Baldwin

Bramhall²,

Ashby³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Drug-induced changes in expression of cytochrome P450 (P450) genes are a significant issue in the preclinical development of pharmaceuticals. For example, preclinically, P450 induction can affect safety studies by reducing the systemic exposure of a compound undergoing toxicological evaluation, thus limiting the exposure that can be safely investigated in patients. Therefore, the induction potential of candidate drugs has been studied as part of the drug development process, typically using protein and/or catalytic end points. However, measuring changes in the levels of mRNA using TaqMan technology offers the opportunity to investigate this issue with the advantages of better dynamic range and specific enzyme identification. Here, we describe the TaqMan application to study ex vivo the P450 gene induction in the rat. Initially, livers from rats dosed with the prototypic P450 inducers ␤-napthoflavone (BNF), phenobarbital (PB), dexamethasone (DEX), and clofibric acid (CLO) were analyzed for mRNA levels of CYP1A1, 1A2, 2B1, 2B2, 2E1, 3A2, 3A23, and 4A1 and compared with control animals. The maximum fold induction of mRNA varied: 2500-fold for CYP1A1 with BNF, 680-fold for CYP2B1 with PB, 59-fold for CYP3A23 with DEX, and 16-fold for CYP4A1 with CLO. This method was then applied to estimate the inductive potential of putative drug candidates undergoing rodent toxicological evaluation. We present a summary of these data that demonstrates the sensitivity and specificity of the TaqMan assay to distinguish between inducers and noninducers and that offers a highly specific alternative to the quantification of drug effects on P450 expression using immunodetection and substrate metabolism.

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“…Most of the studies till date have mainly focused on the body confronting with high xenobiotic load that result in the induction of hepatic phase I and phase II enzymes [23,24]. We hypothesize that increased toxic load of lead and cadmium after early developmental exposure (i.e., in utero and lactational window in the present study) may overwhelm the hepatic biotransformation enzymes of F1 offspring's on reaching adulthood in a sex-dependent manner.…”

Section: Introductionmentioning

confidence: 89%

Sex‐specific effects of gestational and lactational coexposure to lead and cadmium on hepatic phase I and phase II xenobiotic/steroid‐metabolizing enzymes and antioxidant status

Pillai

Patel

Pandya

et al. 2009

J Biochem & Molecular Tox

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Liver has evolved complex enzymatic mechanisms to detoxify a wide array of xenobiotic substances, ranging from dietary components to environmental toxins to pharmaceuticals. Activities of many steroid-metabolizing enzymes in adult rat liver microsomes are sexually differentiated. Toxic effects of lead and cadmium on hepatic tissue have been well established in our earlier studies. We thus monitored the effects of gestational and lactational coexposure to lead and cadmium on hepatic phase I and phase II xenobiotic- and steroid-metabolizing enzyme activities in both male and female F1 generation postnatal day (PND) 56 rats. Adult pregnant female rats were treated subcutaneously [0.05 mg/(kg body wt. day)] with sodium acetate (control group), lead acetate, and cadmium acetate separately and in combination throughout the gestational and lactational period. Hepatic phase I xenobiotic-metabolizing enzymes (NADPH- and NADH-cytochrome c reductase) activities significantly decreased significantly in all the metal-treated groups in both PND 56 male and female rats as compared with the control group. Hepatic phase II enzymes (uridine diphosphate-glucuronosyl transferase, gamma-glutamyl transpeptidase, glutathione-S-transferase, 17-beta-hydroxysteroid oxidoreductase) were also highly susceptible to all the metal-treated groups. The observed alterations in the oxidative stress and biochemical parameters in the liver of F1 generation male and female rats resulted from an independent effect of lead and/or cadmium and also from their interaction. Results suggest that early developmental exposure to lead and cadmium both alone and in combination can suppress the hepatic xenobiotic-metabolizing enzyme activities in the liver of F1 generation male and female rats in a sex-dependent manner.

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Relevance of induction of human drug‐metabolizing enzymes: pharmacological and toxicological implications

Cited by 94 publications

References 39 publications

In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective

In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective

Cytochrome P450 Gene Induction in Rats Ex Vivo Assessed by Quantitative Real-Time Reverse Transcriptase-Polymerase Chain Reaction (Taqman)

Sex‐specific effects of gestational and lactational coexposure to lead and cadmium on hepatic phase I and phase II xenobiotic/steroid‐metabolizing enzymes and antioxidant status

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