INTERINDIVIDUAL VARIABILITY IN THE GLUCURONIDATION OF (S)-OXAZEPAM CONTRASTED WITH THAT OF (R)-OXAZEPAM

Although conjugation with glucuronic acid is a major process for conve rting many xenobiotics into hydrophilic, excretable metabolites, relat ively little has been reported concerning interindividual variability of glucuronidation in human populations. Oxazepam, a therapeutically a ctive metabolite of diazepam, is one of a number of C3-hydroxylated be nzodiazepines for which glucuronide conjugation is the predominant pat hway of biotransformation. The drug is normally formulated as a racemi c mixture of inactive (R) and active (S) enantiomers. In the present s tudy we have investigated the use of oxazepam as a potential probe dru g for studying the variability of glucuronide conjugation, and for dem onstrating the extent to which genetic factors may be responsible, In preliminary studies we determined oxazepam pharmacokinetics metabolite profiles after administration of racemic (R,S) oxazepam to eleven hum an volunteers. The (S) glucuronide was preferentially formed and excre ted in nine of the eleven subjects, The ratios of (S) to (R) glucuroni de metabolites (S/R ratios) were 3.87 +/- 0.79 (mean +/- SD) and 3.52 +/- 0.60 in urine and plasma, respectively. However, both ratios were significantly lower in two subjects (p < 0.01). In these two atypical subjects, the half-life of (R,S) oxazepam was also markedly longer (14 .7 and 15.9 h) than in the other subjects (8.1 +/- 3.2 h). A good corr elation (r(s) = 0.90) between the S/R-glucuronide ratio in urine and t he plasma clearance of (R,S) oxazepam suggested that a low S/R ratio m ay be a marker of poor elimination of oxazepam. In further investigati ons, the drug was administered to 66 additional subjects. The S/R-gluc uronide ratio in 8 h pooled urine was bimodally distributed, with 10% of all subjects possessing ratios below an apparent antimode of 1.9. A survey of the in vitro formation of oxazepam glucuronides by microsom es from 37 human livers also showed that 10% of the livers displayed a n abnormally high apparent Michaelis constant (K-m) for the formation of the (S) glucuronide, but not of the (R) glucuronide. These results suggest that the glucuronidation of the pharmacologically active (S) e nantiomer of oxazepam is decreased in a significant percentage (10%) o f Caucasian individuals. The observed in vitro differences in apparent kinetics of the S-glucuronidation reaction may reflect defects at the genetic level, leading to structural changes in the isozyme(s) of UDP -glucuronyltransferase that catalyse this reaction.