Impact of inter‐individual differences in drug metabolism and pharmacokinetics on safety evaluation

Abstract

Safety evaluation aims to assess the dose-response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is 'without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 10(0.5) (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment.

N-Acetylation of Etamicastat, a Reversible Dopamine-β-Hydroxylase Inhibitor

“…It is recognized that human NAT1 and NAT2 loci are highly polymorphic, with more than 25 alleles identified in each locus (Hein et al, 2000a,b;Stanley and Sim, 2008;Walraven et al, 2008). As an important metabolizing enzyme in humans, the polymorphisms in human NAT expression, especially NAT2, raise concerns about drug-drug interactions related to drug metabolism during clinical use (Spielberg, 1996;Dorne, 2004). Slow and rapid acetylators of both forms of NAT1 and NAT2 were identified in humans (Grant et al, 1991;Meyer, 1994).…”

Effects of Repeated Green Tea Catechin Administration on Human Cytochrome P450 Activity

“…CYP enzyme activities are not changed or reduced moderately in the elderly (>70 years of age; refs. 23,24). In our study, we did not see a significant correlation between each of the CYP indices with age.…”

Human variability in hepatic and renal elimination: implications for risk assessment

“…No reliable data were available for PM subjects in the elderly but data for elderly NPs suggest lower CYP2D6 and CYP2C19 activity compared with healthy adult PMs would be expected (Dorne et al, 2002(Dorne et al, , 2003bDorne, 2004). A recent analysis has demonstrated 50-75% increase in the half-lives of drugs metabolized by cytochrome P450 or eliminated via renal excretion in individuals older than 65 years of age (Ginsberg et al, 2005).…”

“…In quantitative or cancer risk assessments, the human health risk is associated with an estimated exposure or vice versa and these are quantified usually using doseresponse relationships often based on experimental animal data combined with low dose extrapolation (Dorne, 2004). In contrast, for a non-quantitative/non cancer risk assessment, the threshold approach aims to set levels of exposure 'without appreciable health risk' and these are expressed in mg kg −1 of diet per day to relate it to human oral exposure.…”

“…A critical aspect to refine uncertainty factors is to incorporate differences between individuals of the human population (genetic polymorphism, differences between healthy adults, neonates, children and the elderly) at the level of xenobiotic metabolism and elimination (toxicokinetics) as well as at the level of toxicity in the target organism/organ/cell/receptor (toxicodynamics) (Renwick, 1991(Renwick, , 1993Dorne et al, 2001a;Dorne, 2004).…”