Stereochemistry of aromatic phenytoin hydroxylation in various drug hydroxylation phenotypes in humans.

Phenytoin pharmacokinetics exhibit large intersubject differences and coinheritance of phenytoin metabolism with known drug hydroxylation polymorphisms was therefore suspected. To study the inherited enzymatic mechanisms underlying phenytoin disposition in humans, we have investigated the rate and the stereochemical course of aromatic phenytoin hydroxylation in subjects with and without genetic drug hydroxylation deficiencies for mephenytoin or debrisoquine. For the separate analysis of S- and R-enantiomers of 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH; the major phenytoin metabolite), a chiral ligand exchange chromatography system was used. The S-enantiomer of HPPH was the major urinary phenytoin metabolite irrespective of the various drug hydroxylation phenotypes studied. By contrast, the formation of the HPPH R-enantiomer was significantly decreased in poor metabolizer phenotypes of mephenytoin leading to a bimodal distribution of the urinary HPPH S/R-ratio in humans which was correlated closely with the mephenytoin hydroxylation index. Thus, HPPH S/R-values greater than 40 are likely to occur in S-mephenytoin hydroxylation-deficient phenotypes. Analysis of HPPH S/R-ratios in urine samples in a population of 122 randomly selected epileptic patients under chronic phenytoin treatment showed that product-stereoselective aromatic phenytoin hydroxylation is preserved after chronic drug administration. In subjects with and without genetic S-mephenytoin hydroxylation deficiency, extensive HPPH formation was confirmed by a pronounced NIH-shift of the tritium isotope during the product-stereoselective hydroxylation of the pro-S phenyl ring of phenytoin. Substrate-stereoselective glucuronidation of R- and S-HPPH (and related enantiomeric hydantoin metabolites) could be excluded based on identical urinary excretion of p.o. administered pure metabolite enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)