Oxazepam glucuronidation

Patel M, Tang BK, Kalow W. (S)oxazepam glucuronidation is inhibited by ketoprofen and other substrates of UGT2B7. Pharmacogenetics (a) 1995 5 43 19. 

Miners et al. reported an ethnic difference in the His268Tyr (802 C>T) variant (99). In 91 Caucasians, the allele frequency for UGT2B7 2 (802 C>T) was 0.482 versus 0.268 for 84 Japanese subjects. Patel et al. reported a potential polymorphism in the ratio of (R)- and (iS )-oxazepam glucuronides in urine (100). While (J )-oxazepam is a substrate for UGT2B7, the turnover is very low and there was no difference between the UGT2B7 variants in terms of stereoselectivity (99). More recent data indicates that (.Sj-oxazepam is a UGT2B17 substrate. 

Disposition in the Body. Absorbed after oral administration, maximum blood concentrations being attained in 2 to 4 hours bioavailability about 50%. It is metabolised to oxazepam and then to oxazepam glucuronide. 

Disposition in the Body. Readily absorbed after oral administration. About 70 to 80% of a single dose is excreted in the urine in 72 hours almost entirely as oxazepam glucuronide, with only traces of unchanged oxazepam and other minor metabolites. Up to 10% of a dose is eliminated in the faeces, mostly as unchanged drug. 

A single oral dose of 45 mg administered to 8 subjects, produced serum concentrations of 0.88 to 1.44 ig/ml (mean 1.1) of oxazepam in about 2 hours, and concentrations of 0.7 to 1.4pg/ml (mean 0.9) of oxazepam glucuronide in 2 to 4 hours. Daily oral doses of 10 mg every six hours administered to 6 subjects, produced serum concentrations of 0.14 to 0.56 pg/ml (mean 0.3) of oxazepam 2 hours after a dose, and concentrations of 0.22 to 0.40 ig/ml (mean 0.3) of oxazepam glucuronide 4 hours after a... 

Hyperalbuminemia is a relatively rare condition, but hypoalbumin-emia occurs frequently in severe hepatic and renal disorders. In disorders such as these, there may also be relatively elevated serum concentrations of free fatty adds, which may compete with drugs for binding sites on HSA. The S-enantiomer of the glucuronide conjugate of the 1,4-benzodiazepin-2-one drug oxazepam binds to site II on HSA, whereas its antipode binds in an apparently nonspecific manner. The elevated levels of fatty adds found in renally impaired patients can therefore cause a displacement of oxazepam glucuronide (52), which may be enantioselective. 

When stereoisomers are biotransformed by a variety of pathways, differences in the susceptibility of the separate isomers to these pathways result in stereoselectivity for their metabolite patterns. For example, 5-warfarin is oxidized to form primarily 7-hydroxy-5-warfarin, whereas the R enantiomer predominantly undergoes hydroxylation in the 6-position.f Oxazepam glucuronidation is 3-3.4 times higher for the S isomer compared to the R isomer in man and dogs. Biotransformation may generate an additional chiral center in the drug structure and result in diastereo-meric metabolites with markedly different disposition characteristics. 

Ghlordiazepoxide Anxiety alcohol withdrawal 6-27 active metabolites Oxazepam glucuronide... 

Librium, others) Clorazepate preanesthetic medication Anxiety seizure disorders 2 (prodrug) active metabolite Oxazepam glucuronide... 

Tranxene, others) Diazepam (Valium, others) Anxiety status epilepticus. 30-56 Oxazepam glucuronide... 

Oxazepam (Serax) medication Anxiety 5-15 Oxazepam glucuronide... 

Whole-body autoradiography of mice was employed as the technique to study the distribution of diazepam, chlordiazepoxide, and their metabolites. The former con und was more highly localized in body fat thetn the latter however, the rate of penetration of chlordiazepoxide into the brain was slower than that of diazepam. The major metabolite of diazepam was the N-demethylated compound. vitro, in preparations of rat or mouse liver microsomes, the major metabolites of diazepam were N-methyloxazepam or N-demethyldiazepam, respectively. Diazepam inhibited the conversion by mouse liver microsomes of N-methyloxazepam to oxazepam. Prazepam, the cyclopropyl derivative of the N-methyl group of diazepam, was metabolized by the dog in a manner similar to that for dicusepam the major urinairy metabolite was oxazepam glucuronide. ... 

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