Pharmacokinetics of the 5-hydroxytryptamine1A agonist 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OHDPAT) in the rat after intravenous and oral administration.
1. Plasma levels of 3H and unchanged drug were measured in the non-anaesthetized male rat after intravenous (i.v.) or oral administration of (+/-)-(R,S)-[propyl-3H]-8-OHD-PAT, at three dose levels per route of administration. The excretion of conjugated metabolites in bile was also studied following i.v. administration. 2. For unchanged 8-OHDPAT following i.v. administration, terminal t1/2 was 1.56 +/- 0.01 h (mean +/- SD, n > or = 4), kelim 0.45 +/- 0.01 h-1, volume of distribution 0.14 +/- 0.02 litres and clearance 1.10 +/- 0.17 mlmin-1. After oral administration, terminal t1/2, kelim, apparent volume of distribution and clearance were essentially the same when bioavailability was taken into account. Neither dose size nor route of administration had any significant effect on either terminal t1/2 or kelim. Comparison of AUCs following i.v. and oral administration yielded a mean for absolute oral bioavailability of 2.60 +/- 0.24%. 3. Comparison of AUCB for total plasma 3H showed that the extent of absorption was 80.1%, indicating that the low oral bioavailability of 8-OHDPAT is due to first-pass metabolism, rather than poor absorption from the GI tract. 4. Following i.v. administration, irrespective of dose, some 10% of the 3H dose was excreted in the bile in 6 h, 8.5% as 8-OHDPAT-glucuronide and 1.5% as the glucuronide of the N-despropylated metabolite, 8-OHDPAT. The majority of the biliary excretion occurred within 3 h of dosing.
Mason
J P
JP
Department of Pharmacology and Toxicology, St Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK.
Dring
L G
LG
Caldwell
J
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000493:pharmacokinetics*; D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D001682:Biological Availability; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*; D014316:Tritium
D017366:Serotonin Receptor Agonists; D014316:Tritium; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin