Metabolism and disposition of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog.
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.
Tremaine
L M
LM
Drug Metabolism Department, Central Research, Pfizer, Inc., Groton, CT 06340.
Welch
W M
WM
Ronfeld
R A
RA
D015057:1-Naphthylamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008954:Models, Biological; D009281:Naphthalenes / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D020280:Sertraline
D001798:Blood Proteins; D009281:Naphthalenes; D012701:Serotonin; D015057:1-Naphthylamine; D020280:Sertraline