Abstract
Sertaline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- naphthalenamine] is a potent and selective inhibitor of neuronal serotonin uptake and is currently under development for the treatment of depression and of obesity. The drug is greater than 97% bound to plasma proteins, yet extensively distributes into tissues. The whole brain concentration of sertraline in the rat is more than 40-fold higher than that in plasma, and the volume of distribution is about 25 liters/kg in the rat and dog. Sertraline is extensively metabolized by the rat and dog prior to excretion. The metabolic clearance of sertraline is greater than 35 ml of blood/min/kg in each species, and first-pass metabolism occurs with oral administration. Initial metabolic steps include N-demethylation, N-hydroxylation, oxidative deamination, and glucuronidation of sertraline carbamic acid, which in solution is in equilibrium with sertraline and carbon dioxide. The N-desmethyl metabolite, which is 10-fold less potent as an inhibitor of serotonin uptake, is formed in both species. Plasma AUC for desmethyl-sertraline is 66 to 270% of that for sertraline, and is dependent on the species examined and route of drug administration. Sertraline and desmethyl-sertraline undergo oxidative deamination to the corresponding ketone, which is subsequently hydroxylated at the alpha-carbon, forming a diastereomeric metabolite pair. The glucuronides of sertraline carbamic acid, N-hydroxy sertraline, and the alpha-hydroxy ketone diastereomers comprise 45% and 82% of the total radiolabel excreted in urine and bile of bile duct-cannulated rats and dogs, respectively. Bile is the major route of elimination in both species.
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|