Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Debrisoquine is used as an antihypertensive agent, and its 4-hydroxylation is primarily mediated by CYP2D6 (Eiermann et al. 1998; Gonzalez et al. 1988; Woolhouse et al. 1979). Debrisoquine is metabolized to 4-hydroxydebrisoquine, 3-hydroxydebrisoquine, and 1-hydroxydebrisoquine by CYP2D6 (Figure 3.2) (Eiermann et al. 1998), but CYP1A1 may also play a role (Granvil et al. 2002). Mahgoub et al. (1977) have reported one subject who excreted 60.8% of the dose as debrisoquine and only 5.4% as 4-hydroxydebrisoquine, corresponding to a MR of 11.3. Subsequent studies showed this volunteer to be a phenotypic PM, while other three subjects in this study had MRs of 0.5 to 1.4, typical of what is regarded as EMs (Mahgoub et al. 1977). This is the first report showing evidence of the existence of two phenotypes of drug oxidation, EM and PM. The MR of debrisoquine (= amount of debrisoquine/amount of 4-hydroxydebrisoquine in urine collected for 8 h) is used to determine the CYP2D6 phenotype. The bimodal distribution, with an antimode at 12.6 in Caucasian populations (Alvan et al. 1990; Bertilsson et al. 1992; Evans et al. 1980), makes it possible to distinguish between PMs (MR > 12.6) and EMs (MR < 12.6). Phenotype testing with debrisoquine or sparteine provides a cheap, reliable, and direct evaluation of the CYP2D6 metabolic phenotype.
Drugs Affecting Storage and Release from Sympathetic Neurones
Kenneth J. Broadley in Autonomic Pharmacology, 2017
Finally, debrisoquine is well absorbed orally and mostly eliminated within 24 hr, which necessitates twice-daily dosing. Debrisoquine is an interesting drug because of its metabolism to 4-hydroxydebrisoquine by the liver cytochrome P450 mixed-function oxidase system (Table 6.1). There is a marked variation in the ability of individuals to metabolize debrisoquine which has been found to be of genetic origin. The affected cytochrome P450 is CYP2D6. A small (10%) population of poor metabolizers exists who display high sensitivity to the antihypertensive effect of debrisoquine and a low level of the 4-hydroxy metabolite. The genetic control is by a single gene pair and poor metabolism is a recessive trait arising in homozygous recessive children of heterozygous extensive-metabolizing parents. Debrisoquine is therefore a useful model for evaluating whether an individual has a genetic difficiency in the metabolism of related drugs that undergo 4-hydroxylation. Of relevance to drugs in this book, these include guanoxan, metoprolol, timolol, nontriptyline and bufanolol. In poor metabolizers, there is potential for increased potency and side-effects of several β-blockers; however in practice this may be only reflected in more patient discomfort leading to poor compliance (Meyer 1994, Tucker 1994).
General toxicology
Timbrell John in Study Toxicology Through Questions, 2017
(d) Disease may be a factor which influences the toxicity of a chemical. Thus liver disease will tend to decrease the metabolism of some, although not all, drugs. By reducing the level of proteins such as plasma albumin, which is synthesised in the liver, liver disease may also affect the distribution of a drug and hence its toxicity. Similarly renal disease will alter the excretion of drugs and hence may increase toxicity. Disease may also affect the physiology and/or biochemistry of the body and therefore influence the metabolism or disposition of a drug in unexpected ways. A7. (a) Cytochrome P450 2D6 is one of the isoenzymes of the cytochrome P450 system. It is responsible for catalysing the hydroxylation of debrisoquine and a number of other drugs. There are variations in the activity of this isoenzyme in the human population resulting from a mutation leading to an isoenzyme with reduced activity. Therefore individuals may be classified as extensive or poor metabolisers (hydroxylators) of debrisoquine. Poor metabolisers of debrisoquine have an exaggerated hypotensive effect after a therapeutic dose of the drug. With certain other drugs metabolised by this isozyme, poor metabolisers tend to have a greater susceptibility to certain adverse effects.
Cytochrome P450: genotype to phenotype
Published in Xenobiotica, 2020
CYP2D6 shows even more variation; frameshifts (*3, *6) give decreased metabolism of debrisoquine or a non-functional enzyme respectively while splicing defects (*4, *41) decrease metabolism of bufuralol and dextromethorphan. CYP2D6*5 leads to a deleted enzyme and other SNPs are associated with reduced metabolism of sparteine, metoprolol and dextromethorphan (Annalora et al., 2017; Wang et al., 2014). Although CYP2D6 expression in the liver is only ∼2%, many drugs, including beta-blockers, antiarrhythmics, opiates and tricyclic antidepressants, are metabolised by this isoform and ∼10% of a Caucasian population will potentially suffer adverse effects unless the drug dosage is tailored to the patient. A PM patient would receive no therapeutic benefit if the metabolite is the active form, but an EM or UM patient would be more likely to show adverse reactions. Allele frequencies differ considerably across ethnic groups, and PM status varies between 0.4% and 5.4% across world populations.
Phenylalanine 4-monooxygenase: the “sulfoxidation polymorphism”
Published in Xenobiotica, 2020
Stephen C. Mitchell, Glyn B. Steventon
Initially, it was assumed that the phenomenon of poor S-carboxymethyl-l-cysteine sulfoxidation and inefficient debrisoquine 4-hydroxylation (later shown to be cytochrome P450 2D6 mediated) was linked (Waring et al., 1981) but this was found not to be the case (Haley et al., 1985). Ideas concerning the potential involvement of the flavin-containing monooxygenases, the other major xenobiotic metabolising system located within the artefactual microsomal component, were also abandoned as a compound possessing two negative charges at physiological pH with one of these, a carboxyl group just one methylene bridge away from the oxidizable sulfur moiety, would not be a substrate (Taylor & Ziegler, 1987; Ziegler, 1980). Subsequent studies demonstrated that the sought catalytic activity resided solely within the cytosolic fraction of the disrupted cell. This was confirmed using hepatic cytosol obtained from the rat, rabbit, guinea pig, hamster, sheep, whale and human (Waring, 1989; Waring et al., 1986) and has since been demonstrated in the mouse and dog and reconfirmed in human (Boonyapiwat et al., 2008; Panagopoulos et al., 2015; Steventon & Mitchell, 2018).
Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects
Published in Drug Metabolism Reviews, 2020
Ana Rita Silva, Ricardo Jorge Dinis-Oliveira
Similarly to the above described Caucasian study, a population of 75 healthy Japanese subjects was phenotyped using the metabolic ratio to determine the percentage of PM. The study concluded 1–3% of the population were PM (Nagai et al. 1996). Moreover, differences in the pharmacokinetics between European Caucasians and Japanese EM were identified, namely larger 3-hydroxymorphinan formation in the Japanese population (Nagai et al. 1996). East Asian populations present the lowest incidence of poor metabolism (0–2%) (Gaedigk 2013). For Caucasians, this value was first obtained using sparteine or debrisoquine as the test compound and was estimated to be 3–10% (Küpfer and Preisig 1983). Subsequently, using DXM as a CYP2D6 O-demethylation probe, the frequency of PM in a white French population was 3.9%, meaning that Caucasians Europeans are the group with higher incidence (3–10%) for the PM phenotype (Larrey et al. 1987; Gaedigk 2013). Indeed, Black Africans and African Americans have a 2–7% incidence of PM (Gaedigk 2013).
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