Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment

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Abstract

CYP3A4 constitutes the major liver cytochrome P450 isoenzyme and is responsible for the oxidation of more than 50% of all known drugs. Human variability in kinetics for this pathway has been quantified using a database of 15 compounds metabolised extensively (>60%) by this CYP isoform in order to develop CYP3A4-related uncertainty factors for the risk assessment of environmental contaminants handled via this route. Data were analysed from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration–time curve (AUC)] and acute exposure (Cmax). Interindividual variability in kinetics was greater for the oral route (46%, 12 compounds) than for the intravenous route (32%, 14 compounds). The physiological and molecular basis for the difference between these two routes of exposure is discussed. In relation to the uncertainty factors used for risk assessment, the default kinetic factor of 3.16 would be adequate for adults, whereas a CYP3A4-related factor of 12 would be required to cover up to 99% of neonates, which have lower CYP3A4 activity.

Introduction

Among the various CYP gene families, the CYP3A subfamily accounts for the majority of cytochrome P450 enzymes present in the adult human liver and intestine. There are at least three functional enzymes, CYP3A4, CYP3A5 and CYP3A7, the genes for which are located on chromosome 7. These isoforms possess high sequence homology (85%) but differ in substrate specificity and expression. CYP3A4 has been recognised as the most abundant of them representing 30–40% of the total CYPs in the liver and 50% of the total CYPs in midzonal and centrolobular regions. The intestinal CYP3A is present in the enterocytes lining the lumen of the small intestine (de Wildt et al., 1999). The intestine also contains the MDR 1 (multi drug resistance) P-glycoprotein, which has overlapping substrate specificities with CYP3A4 (Wacher et al., 1995). CYP3A4 substrates may act as substrates, inhibitors or enhancers of P-glycoprotein (Wacher et al., 1995, Sowunmi et al., 1995) and interaction with P-glycoprotein may decrease oral biovailability and absorption of drug and other xenobiotics (Suzuki and Sugiyama, 2000).

The CYP3A4 isoform oxidises, at least in part, 50% of drugs for which suitable data are available, including structurally unrelated substrates such as antihistamines, anticonvulsants, antimicrobials, antifungals, immunosupressants, benzodiazepines, antihypertensives, anti-arrhythmics, antidepressants, analgesics, and anaesthesics, as well as procarcinogens such as aflatoxin B1 (Shimada and Guengerich, 1989). The pesticides chlorpyrifos, parathion and diazinon are also oxidised in part by the CYP3A4 isoform to their toxic metabolites, which are a potent acetylcholinesterase inhibitors (Sams et al., 2000). Endogenous substrates include many steroids such as testosterone (2β-, 6β- and 15β-hydroxylation), androstanedione (6β-hydroxylation), cortisol, progesterone, and estradiol (de Wildt et al., 1999).

Because CYP3A4 has a broad substrate specificity, it is of considerable importance in risk assessment. The analysis of human variability in kinetics for this pathway would provide a basis for the development of uncertainty factors for the risk assessment of non-nutrients handled by this CYP isoform.

A 100-fold uncertainty factor has been used in the risk assessment of threshold toxicants for the past 40 years, which is the product of a 10-fold factor for interspecies differences and a 10-fold factor for human variability (WHO, 1987). Each factor has been subdivided to allow chemical-specific toxicokinetic and toxicodynamic data to be used quantitatively in the risk assessment process (Renwick, 1993). Values of 100.5 (3.16) have been proposed for human variability in toxicokinetics and toxicodynamics (IPCS, 1994, IPCS, 1999). Pathway-related uncertainty factors for toxicokinetic aspects (Renwick and Lazarus, 1998) have been developed, for interspecies differences and human variability in metabolism by CYP1A2 (Dorne et al., 2001a, Walton et al., 2001a), glucuronidation (Dorne et al., 2001b, Walton et al., 2001b) and the polymorphic CYP2D6 (Dorne et al., 2002). Potentially sensitive subgroups of the human population have been identified for each pathway (i.e. neonates for all three pathways, poor metabolisers for CYP2D6). Pathway-related uncertainty factors have been calculated that cover 95, 97.5 or 99% of each subpopulation in order to provide several risk management options (Dorne et al., 2001a, Dorne et al., 2001b, Dorne et al., in press).

The present paper describes the analysis of human variability in kinetics for the CYP3A4 pathway of metabolism in order to quantify inter-individual differences in the healthy adult population, to characterise the magnitude of any differences in potentially susceptible subgroups of the population, and to derive CYP3A4-related uncertainty factors.

Section snippets

Materials and methods

The methods used in this paper have been described previously (Dorne et al., 2001a, Dorne et al., 2001b, Dorne et al., in press).

Metabolism data for CYP3A4 probe substrates

The literature review identified 12 CYP3A4 substrates that fulfilled the criteria after oral dosage (alprazolam, budesonide, cisapride, diltiazem, felodipine, lidocaine, midazolam, nifedipine, nisoldipine, terfenadine, triazolam and zolpidem), data following iv dosage were also available for most of these substrates. Intravenous data only were used for three substrates (alfentanil, cyclosporin and erythromycin) because they showed incomplete absorption after oral dosage. A summary of the

Discussion

Two large databases describing the pharmacokinetics for 15 major substrates handled by CYP3A4 were analysed for healthy adults using parameters reflecting chronic exposure (clearances/AUC data after oral and iv dosage to 1381 and 999 subjects, respectively) and oral acute exposure (Cmax data for 1238 subjects). The variability in kinetics for markers of chronic exposure in healthy adults was larger for the oral route of exposure (46%) compared with the iv route (32%). The differences in

Acknowledgements

The authors are grateful to the Department of Health (UK) and the Health and Safety Executive (UK) for jointly funding this work.

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    Present address: School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK.

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