Ross Crabtree

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.

Pergolide, a potent long‐acting dopamine‐receptor agonist

After single doses (100 to 400 µg orally), pergolide, a synthetic ergot, reduced basal plasma prolactin levels in normal subjects in a dose‐related manner. This effect persisted for more than 24 hr. Multiple doses of pergolide (150 to 250 µg daily for 7 days) resulted in a plasma prolactin decrease of more than 80%. A single dose of pergolide (150 µg orally) suppressed plasma prolactin and abolished the plasma prolactin diurnal rhythm, i.e., suppression of sleep‐induced elevation in plasma prolactin during a 40‐hr period. Perphenazine (5 mg intramuscularly)–induced plasma prolactin elevation was inhibited by pergolide; the effect was dose dependent. After single or multiple doses, pergolide had no effect on plasma follicle‐stimulating hormone, luteinizing hormone, Cortisol, growth hormone, and thyroid‐stimulating hormone. Pergolide appears to have specificity at the pituitary level for the dopamine receptors that mediate prolactin secretion.

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.

Effects of fenoprofen and aspirin on gastrointestinal microbleeding in man.

The 51Cr‐labeled erythrocyte assay was used to compare the effects of equipotent doses of fenoprofen and aspirin—600 mg.:1 Gm.; 400 mg.:650 mg. Based on the appearance of label in the feces of normal men, we conclude that (1) both fenoprofen and aspirin produced measurable gastrointestinal microbleeding in man and (2) the amount of microbleeding after fenoprofen was significantly less than that after the aspirin preparations used in this study.

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.

Clinical response of patients with galactorrhea to pergolide, a potent, long-acting dopaminergic ergot derivative

Abstract Pergolide is an ergot derivative with dopaminergic activity and, like bromocriptine, can suppress prolactin release from the pituitary gland. In a single blind study pergolide was administered for 90 days to three females with idiopathic hyperprolactinemia manifested by galactorrhea and amenorrhea. Response to therapy was followed clinically and by determination of plasma prolactin concentrations. Pergolide lowered plasma prolactin concentrations and suppressed galactorrhea in all patients. Menstruation recurred in both patients with intact GU systems. Side effects were minor and tolerance developed to all but nasal stuffiness. Pergolide appears to be efficacious therapy for patients with amenorrhea/galactorrhea secondary to hyperprolactinemia.

Tracer microspheres as a fecal marker in balance studies

The use of radio labeled microspheres as fecal markers was investigated and compared in vivo to chromium sesquioxide and β‐sitosterol. They proved to be chemically inert, uniformly distributed in feces, and fully recoverable. The advantages over the other markers include minimal handling of specimen and direct measurement without complex analytic procedures.

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.