Küpfer A, Desmond P, Patwardhan R, Schenker S, Branch R A
Clin Pharmacol Ther. 1984 Jan;35(1):33-9. doi: 10.1038/clpt.1984.5.
Deficient aromatic hydroxylation of S-mephenytoin was observed in an index subject during a kinetic study of stereoselective metabolism of mephenytoin. A genetic basis for this defect was suggested by decreased urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother had urinary recoveries of 4-OH-M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with four normal subjects after a single oral dose of differentially radiolabeled pseudoracemic mephenytoin (5 microCi of 14C-S-mephenytoin, 45 microCi of H3-R-mephenytoin, and 11.5 mumol/kg of both S- and R-mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the next 4 days. In normal subjects, there was substrate stereoselective metabolism with the S-enantiomer rapidly excreted as 4-OH-M and the R-enantiomer slowly excreted as 5-phenyl-5-ethylhydantoin (PEH). Stereoselective metabolism persisted during repeated dosing. In the hydroxylation-deficient subject, there was no evidence of stereoselective metabolism, recovery of 4-OH-M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S-mephenytoin results in the S-enantiomer metabolization by the alternate route of demethylation to PEH that cumulates, thereby, in comparison to the normal, effectively doubling the dose of total hydantoin.
在美芬妥因立体选择性代谢的动力学研究中，一名索引受试者被观察到S-美芬妥因的芳香族羟基化作用不足。在该索引受试者的两名兄弟口服外消旋美芬妥因后24小时内，3-甲基-5-(4-羟基苯基)-5-乙基乙内酰脲(4-OH-M)的尿回收率降低，提示了这种缺陷的遗传基础。父母和第三个兄弟的4-OH-M尿回收率与20名正常受试者组中的情况处于同一水平。在索引受试者中研究了这种缺陷的动力学影响，并与四名正常受试者进行了比较。这些正常受试者单次口服差异放射性标记的假外消旋美芬妥因(5微居里的14C-S-美芬妥因、45微居里的H3-R-美芬妥因以及11.5微摩尔/千克的S-和R-美芬妥因)，随后在接下来的4天里每天单次口服1.4毫摩尔未标记的外消旋美芬妥因。在正常受试者中，存在底物立体选择性代谢，S-对映体迅速以4-OH-M形式排泄，R-对映体缓慢以5-苯基-5-乙基乙内酰脲(PEH)形式排泄。重复给药期间立体选择性代谢持续存在。在羟基化缺陷受试者中，没有立体选择性代谢的证据，4-OH-M的回收率很低，两种对映体都缓慢排泄，主要以PEH形式。血浆PEH浓度和尿PEH排泄率约为正常受试者的两倍。因此，S-美芬妥因羟基化能力的遗传缺陷导致S-对映体通过脱甲基的替代途径代谢为PEH，PEH会累积，从而与正常情况相比，有效地使总乙内酰脲剂量增加一倍。
