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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Mephenytoin has been used as a probe substrate to determine CYP2C19 phenotype in humans. (S)-(R)-mephenytoin undergoes rapid hydroxylation to form (S)-4 hydroxymephenytoin (SOHP) with the slower formation of (R)-ethylhydantoin (PEH). The ratio of SOHP to PEH is used as a measure of CYP2C19 activity [39]. The test in adults involves the administration of 100 mg mephenytoin followed by the collection of urine for 8 hours post dose [40,41]. Although mephenytion has been administered to children [42], this test has so far not been applied to a paediatric population, possibly because of worries about toxicity [42,43]. Otherwise, the test is relatively non-invasive. Stability issues have been raised regarding the assessment of CYP2C19 activity based on the SOHP to PEH ratio [44].
Antiepileptic Drugs Useful in the Treatment of Tonic-Clonic and Partial Seizures
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
The usual adult dose of mephenytoin is 400 to 800 mg/day. Mephenytoin is rapidly metabolized to nirvanol, which has similar antiepileptic and toxic properties.63 The therapeutic range for nirvanol is 25 to 40 μg/ml. Nirvanol has a biological half-life of 96 to 141 h.64 Full drug effect may therefore not occur until up to 2 weeks after starting mephenytoin or after any change in its dose.
Pirfenidone 5-hydroxylation is mainly catalysed by CYP1A2 and partly catalysed by CYP2C19 and CYP2D6 in the human liver
Published in Xenobiotica, 2021
Yongjie Zhang, Rei Sato, Tatsuki Fukami, Masataka Nakano, Miki Nakajima
In HLM from different donors, a strong correlation was observed between pirfenidone 5-hydroxylase and phenacetin O-deethylase activities (Figure 5(A)), suggesting that CYP1A2 is mainly involved in pirfenidone hydroxylation in HLM. In addition, a relatively weak but still significant correlation with S-mephenytoin 4′-hydroxylase activity (Figure 5(C)) was observed. Unexpectedly, a significant correlation was observed between phenacetin O-deethylase and S-mephenytoin 4′-hydroxylase activities (r = 0.54, P < 0.05, Supplementary Figure S2) because one sample had the highest phenacetin O-deethylase and S-mephenytoin 4′-hydroxylase activities. Therefore, the involvement of CYP2C19 could not be verified by the correlation analysis. The lack of correlation with coumarin 7-hydroxylase activity (Figure 5(B)) suggested that the contribution of CYP2A6 to pirfenidone 5-hydroxylation in human livers would be minimal, although recombinant CYP2A6 showed a similar Km value as pirfenidone 5-hydroxylase activity to HLM. The bufuralol 1′-hydroxylase activity was also not significantly correlated with the pirfenidone 5-hydroxylase activity (Figure 5(D)). Collectively, these data indicated that CYP1A2 was the primary enzyme for pirfenidone metabolism in human liver.
Evaluation of the effect of Bovis Calculus Artifactus on eight rat liver cytochrome P450 isozymes using LC-MS/MS and cocktail approach
Published in Xenobiotica, 2021
Yun-Jing Zhang, Wen-Li Zhou, Fei Yu, Qian Wang, Can Peng, Jia-Yi Kan
The simultaneous incubation of substrates may lead to substrate interactions and inhibition of CYP activity by the solvent. So we used the concentrations of the substrates below their respective Michaelis constants to minimize the interactions and used organic solvents at low concentration (<1% (volume/volume)). Phenacetin had no effect on the metabolism of other probe drugs when it was lower than 152 μM. In this experiment, the concentration of phenacetin was 150 μM. Bupropion is the preferred probe drug for CYP2B6 and has been used in many cocktail methods and has no effect on the activities of other isozymes when less than 100 μM. According to the Km value of bupropion (67–168 μM), the concentration of bupropion is selected to be 95 μM, and 2.4 μM for amodiaquine (Km values: 2.6 μM). For tolbutamide, the concentration was set at 109 μM (Km values: 67–838 μM). The concentration of S-mephenytoin was set at 50 μM according to the Km value of (78 μM). As probe drug of CYP2D6, dextromethorphan has no effect on other probe drugs when the concentration is lower than 25 μM. In this study, the concentration of dextromethorphan is 10 μM. Midazolam was selected as a CYP3A4 probe drug with a concentration of 32 μM. When the concentration of chlorzoxazone is less than 50 μM, it has no effect on other subtypes of enzymes. In this experiment, the concentration of chlorzoxazone is 15 μM (Xia et al. 2021; Yang et al. 2014).
Impact of cytochrome P450 variation on meperidine N-demethylation to the neurotoxic metabolite normeperidine
Published in Xenobiotica, 2020
Jessica L. Murray, Susan L. Mercer, Klarissa D. Jackson
In order to compare rates of normeperidine formation with a validated marker reaction for assessment of CYP2C19 enzyme activity in individual donors, rates of S-mephenytoin 4′-hydroxylation were determined in pooled and CYP2C19-genotyped human liver microsomes using previously published methods (Walsky & Obach, 2004). (S)-Mephenytoin (60 µM) was incubated with pooled human liver microsomes and eighteen individual CYP2C19-genotyped human liver microsomes (0.2 mg protein/ml) for 40 min. Reactions were quenched with the addition of 0.4 ml of ice-cold methanol containing 2 µM 4′-hydroxymephenytoin-d3 and prepared via centrifugation (3740 x g at 4 °C) for 20 min prior to LC-MS/MS analysis. Formation of 4′-hydroxymephenytoin was quantified by comparison to an eight-point standard curve containing commercial synthetic 4′-hydroxymephenytoin in the range of 50–10,000 nM. Standard curves were prepared each day following experiments using previously made 4′-hydroxymephenytoin stock solutions stored at −20 °C.