Pharmacokinetics of the 5-hydroxytryptamine_1A agonist 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OHDPAT) in the rat after intravenous and oral administration

Abstract

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 t_1/2 was 1.56 ± 0.01 h (mean ± SD, n±4), k_elim 0.45 ± 0.01 h⁻¹, volume of distribution 0.14 ± 0.02 litres and clearance 1.10 ± 0.17 ml min⁻¹. After oral administration, terminal t_1/2, k_elim 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 t_1/2 or k_elim. Comparison of AUCs following i.v. and oral administration yielded a mean for absolute oral bioavailabiltty of 2.60 ± 0.24%.

3. Comparison of AUCs 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 6h, 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.