The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects. In the 0-6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47,779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary 14C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47,779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favouring the S-configuration of GP 47,779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.

1. The anti-inflammatory agent diclofenac sodium (o-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium salt) is extensively metabolized by rat, dog, baboon and man. The main metabolites were isolated from the urine of all species and from the bile of rat and dog and identified by spectroscopy. 2. Metabolism involves direct conjugation of the unchanged drug, or oxidation of the aromatic rings usually followed by conjugation. Sites of oxidation are either position 3' or 4' of the dichlorophenyl ring or, alternatively, position 5 of the phenyl ring attached to the acetic acid moiety. 3. In the urine of rat, baboon and man conjugates of the hydroxylated metabolites predominate, but the major metabolite in dog urine is the taurine conjugate of unchanged diclofenac. 4. In the bile of rat and dog, the main metabolite is the ester glucuroniade of unchanged diclofenac.

No abstract

1. Quantitative determinations of unchanged diclofenac and two of its major phenolic metabolites were made by reverse isotope dilution analysis on urine of rat, dog, rhesus monkey, baboon and man and on bile of rat, dog and man. Isotope dilution analysis was performed before and after various methods of enzymic and chemical hydrolysis. 2. The same samples were also analysed by two-dimensional t.l.c. and subsequent autoradiography, to estimate the remaining phenolic metabolites. 3. In contrast to rat, rhesus monkey, baboon and man, which excrete mainly hydroxylated metabolites, the dog does not oxidize diclofenac. Dog urine contained a relatively stable taurine conjugate of diclofenac, and in the bile an ester glucuronide was excreted, which decomposed even in weakly alkaline soln. 4. The unstable ester glucuronide found in dog bile was also demonstrable in rat bile. It presumably hydrolyses in the duodenum, releasing diclofenac which undergoes enterohepatic circulation.

No abstract