Howard Rowe

11-Hydroxy-Δ9-tetrahydrocannabinol: Pharmacology, Disposition, and Metabolism of a Major Metabolite of Marihuana in Man

11-Hydroxy-Δ9-tetrahydrocannabinol, administered intravenously to man, produces psychologic and pharmacologic effects that persist for several hours. The drug and its metabolites are excreted in urine and feces for more than 1 week. The pharmacology, disposition, and metabolism of 11-hydroxy-Δ9-tetra-hydrocannabinol mimic that of Δ9-tetrahydrocannabinol, thus providing evidence that Δ9-tetrahydrocannabinol (the major active component of marihuana) is converted to the 11-hydroxy compound in man, the latter compound being responsible for the effects.

Fluoxetine, a selective serotonin uptake inhibitor.

Fluoxetine is a selective serotonin uptake inhibitor in man. Platelets harvested from subjects to whom fluoxetine was administered (30 mg daily for 1 wk) had a diminished ability to accumulate 3H‐serotonin. The inhibition of uptake was positively correlated with the plasma concentrations of fluoxetine. Plasma from fluoxetine‐treated subjects also inhibited the uptake of 3H‐serotonin by platelets obtained from nontreated subjects. Fluoxetine was without effect on the noradrenergic nerve endings; pressor effects induced after the administration of norepinephrine or tyramine were similar whether subjects were receiving fluoxetine or placebo. Fluoxetine administration for 30 days produced similar pharmacologic effects as after the 7‐day study and included: (1) no change in sensitivity to the pressor effects of tyramine and norepinephrine and (2) marked inhibition in the uptake of 3H‐serotonin by platelets harvested from subjects on this regimen. In addition, fluoxetine caused a diminution of the concentration of endogenous serotonin in platelets, resulting in serotonin levels of only 20% of control. Fluoxetine was well absorbed and achieved peak plasma concentration at 6 hr after administration. Fluoxetine and the major metabolite, norfluoxetine, appeared to reach a steady state within 12 to 14 days. Fluoxetine, administered in single doses of 1 to 90 mg produced no behavioral or adverse effects. Similarly, after 1 wk of fluoxetine administration, no behavioral or adverse effects were observed.

Physiologic disposition of nabilone, a cannabinol derivative, in man.

Nabilone is a cannabinoid that is being evaluated in man as a potentially useful psychoactive drug. We found that nabilone was readily absorbed from the human gastrointestinal tract when administered orally as a coprecipitate with polyvinyl‐pyrrolidone. The absorbed drug disappearedfrom plasma rather rapidly (half‐life, approximately 2 hr), evidently due to extensive tissue distribution and rapid metabolism. The metabolites of nabilone persist in plasma for extended periods (half‐life of total radioactivity exceeds 20 hr). Circulating metabolites include isomeric carbinols formed by reduction of the ketone in the 9‐position of nabilone. Nabilone is eliminated in feces (about 65% of dose) and urine (20%). The excretory products in urine have not been identified, but metabolites that are labile to hydrolysis by β‐glucuronidase or sulfatase do not appear to be formed in signijicant amounts. A metabolite of nabilone in fixes has been identified as a diol formed by reduction of the 9‐keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. The long duration of action of nabilone in the face of rapid and extensive metabolic elimination suggests that the pharmacologic effects, at least in part, may be exerted by one or more active metabolites.

Effect of fluoxetine on psychomotor performance, physiologic response, and kinetics of ethanol.

The effects of fluoxetine, a specific serotonin reuptake inhibitor, on the psychomotor performance, physiologic response, and kinetic disposition of ethanol were examined. Fluoxetine (30 or 60 mg) with ethanol (45 ml absolute alcohol per 70 kg body weight) did not alter the plasma or blood concentrations of fluoxetine or ethanol, respectively, when compared with levels after either drug alone. There was no significant effect on standing or recumbent blood pressure or heart rate after single or multiple doses of fluoxetine alone or in the combination. Single or multiple doses of fluoxetine had no effect on the psychomotor activity (stability of stance, motor performance, or manual coordination) or subjective effects of alcohol. Data indicate that fluoxetine does not inhibit ethanol metabolism nor does it have any effects on its psychomotor activity.

The effect of fluoxetine on warfarin metabolism in the rat and man

Abstract Fluoxetine, a selective blocker of serotonin uptake, inhibits the metabolism of warfarin in rats. In contrast, after a single dose or seven daily doses of fluoxetine to human subjects, no inhibition of warfarin metabolism was observed.

Pharmacologic effects and physiologic disposition of delta 6a,10a dimethyl heptyl tetrahydrocannabinol (DMHP) in man.

14C‐DMHP (200 µg/70 kg man) was administered by the intravenous route to 3 healthy male casual marihuana smokers. Tachycardia occurred within 10 minutes and persisted for from 11 1/2 to 6 hours. Blood pressure fell slightly with time when subiects were supine, while standing for less than 1 minute resulted in marked hypotension. In these 3 subjects, except for dizziness on standing there were essentially no demonstrable psychologic effects, neither euphoria nor dysphoria. Subiects did, however, report symptoms similar to those after marihuana or Δ9‐THC, including dry mouth, decreased salivation, and drowsiness. After intravenous dimethyl heptyl tetrahydrocannabinol (DMHP), plasma levels of total radioactivity and 14C‐DMHP declined in a multiphasic fashion; the half‐life of the terminal phase for DMHP was 39 hours. Approximately 69% of the administered radioactive dose was recovered in 7 days. Radioactivity was excreted predominantly in the feces (58%) and to a lesser extent in urine (11%) during the 7 day collection period.

Tetrahydrocannabinols and serum prolactin levels in man

Abstract δ 9 -THC, 11-OH-δ 9 -THC or placebo was administered to casual marihuana smokers in a double-blind, crossover study. δ 9 -THC and 11-OH-δ 9 -THC produced marked pharmacologic and psychologic effects (tachycardia, increased symptom score and psychologic high). In contrast to effects produced by many other centrally acting drugs, the acute administration of these cannabinoids was devoid of any significant effect on prolactin secretion as determined by monitoring changes in serum prolactin levels.

Physiologic disposition of lergotrile

Lergotrile, an ergot alkaloid, has been shown to be effective in treating disorders associated with elevated serum prolactin levels (e.g., galactorrhea‐amenorrhea). Lergotrile has also been found to be a potent dopaminergic agonist and thus to be effective in Parkinsons disease. This study describes the physiologic disposition of lergotrile after administration to human volunteers. N‐14CH3‐lergotrile was rapidly absorbed from the gastrointestinal tract. Lergotrile was detected at low concentrations in plasma when subjects received large doses over extended periods of time. The major portion of radioactivity in plasma was allributed to the presence of circulating metabolites of lergOlrile. Lergotrile metabolites were eliminated in the feces (ca. 60%), urine (ca. 20%), and breath (ca. 7% as 14CO2). A metabolite in feces was identified as 13‐OH‐lergotrile (up 10 30% of the dose). A metabolite in urine was formed by conversion of the C8‐acetonitrile group of lergotrile to a carboxyl group (aboUl /0% of the dose). The presence of 14CO2 in the expired air after administering N‐14C‐methyl‐lergotrile indicated that the drug was N‐demethylated to form norlergotrile.