Date of Award

1-1-1983

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology and Pharmacology

Abstract

To determine the effects of (DELTA)('9)-tetrahydrocannabinol (THC) on the pharmacokinetics and metabolism of phencyclidine (PCP) or methaqualone (MTQ), both in vivo and in vitro studies were conducted using Sprague Dawley rats. For the in vivo studies rats received THC (10 mg/kg, p.o.) 90 minutes prior to the administration of ('3)H-PCP(.)HCl (7.5 mg/kg, i.p.) or ('14)C-MTQ (25 mg/kg, i.p.). These doses were used throughout except for the following PCP studies; biliary excretion (3 mg/kg, i.p.) and urinary excretion of PCP metabolites (15 mg/kg, i.p.). Controls received sesame oil (2 ml/kg, p.o.), the vehicle for THC in test cases, 90 minutes prior to the injection of PCP and MTQ. Plasma levels of ('3)H-PCP(.)HCl equivalents were significantly altered by the administration of THC, with the test curve elevated and parallel to the control. Tissue data followed the same pattern as plasma. The urinary, fecal, and biliary excretion of ('3)H-PCP(.)HCl equivalents for the most part did not show significant perturbation with the coadministration of THC. The trend, however, was in the direction of elevated excretion of ('3)H-PCP(.)HCl equivalents for test animals. With respect of MTQ, plasma studies indicated that THC could significantly elevate ('14)C-MTQ equivalents for the first 4.5 hours, reduce these levels from approximately 6.5 to 16.5 hours, and again elevate the levels above controls for the period from 19.5 to 22.5 hours. All significant changes in tissue levels mirrored plasma value differences seen between test and control animals. Biliary excretion data indicated that THC showed a trend towards altering the active excretion of ('14)C-MTQ equivalents. Such alterations, however, were not found to be significant.In vitro microsomal metabolism studies indicated that THC at the 0.1, 0.05, 0.025, 0.0125, and 0.00625 mM concentrations altered the production of the following metabolites of PCP; 1-phenylcyclohexylamine, 1-(1-phenyl-4-hydroxycyclohexyl)piperidine, and 1-(1-phenylcyclohexyl)-4-hycroxypiperidine. Similar studies conducted with MTQ revealed that THC at the 0.05, 0.025, and 0.0125 mM levels also inhibited the metabolism of this compound.

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