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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
CYP2D6. This polymorphism has been thoroughly explored and was discovered following therapeutic accidents occurring with the use of debrisoquine for hypertensive adults [5]. More than 50 mutations and 70 different “poor metaboliser” alleles have been described, with large ethnic differences in frequency [6]: 7 to 10% of Caucasians and 1 to 2% of Asians are poor metabolisers, while 2 to 3 % are ultrarapid metabolisers, due to gene duplications or gene multiplications [7].
Substrates of Human CYP2D6
Published in Shufeng Zhou, 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
Published in Kenneth J. Broadley, 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).
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).
Analysis of the urinary metabolic profiles in irradiated rats treated with Activated Protein C (APC), a potential mitigator of radiation toxicity
Published in International Journal of Radiation Biology, 2023
Shivani Bansal, Sunil Bansal, Brian L. Fish, Yaoxiang Li, Xiao Xu, Jose A. Fernandez, John H. Griffin, Heather A. Himburg, Marjan Boerma, Meetha Medhora, Amrita K. Cheema
All LC-MS grade solvents including acetonitrile and water were purchased from Fisher Optima grade, Fisher Scientific. High purity formic acid (99%) was purchased from Thermo-Scientific. Debrisoquine and 4-nitrobenzoic acid were purchased from Sigma-Aldrich. EquiSPLASH® LIPIDOMIX® quantitative mass spec internal standard and 15:0–18:1-d7-PA, C15 Ceramide-d7 (d18:1-d7/15:0) and 18:1 Chol (D7) ester were purchased from Avanti polar lipids. Internal standard for free fatty acid (FFA), dihydroceramides (DCER), hexosylceramides (HCER), lactosylceramides (LCER) were purchased from Sciex as Lipidyzer platform kit. The LC-MS data acquisition details are provided in Supplementary data.
In vitro inhibition and induction of human liver cytochrome P450 enzymes by a novel anti-fibrotic drug fluorofenidone
Published in Xenobiotica, 2021
Linling Li, Xi Luo, Zeneng Cheng
In microsomes, the concentrations of midazolam and 1′-hydroxymidazolam were determined by the HPLC method developed by Lehmann and Boulieu (1995). Debrisoquine and 4-hydroxydebrisoquine were assayed with the HPLC-UV detection of Cifuentes et al. (1997). Tolbutamide, mephenytoin and their hydroxymetabolites were analyzed according to previously described methods (Lasker et al. 1998). Caffeine and 1,7-dimethylxanthine, chlorzoxazone and 6-hydroxychlorzoxazone were detected using HPLC determination as reported in previous studies (Giri et al. 2002; Sheng et al. 1998).