Chemical formula: C₂₁H₃₀O₂ Molecular mass: 314.462 g/mol PubChem compound: 16078
Dronabinol is an orally active cannabinoid which has complex effects on the CNS, including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol.
Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter-patient variability. After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.
Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N=12) received 210 mg per day of dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.
Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol. In clinical studies involving AIDS patients, the appetite stimulant effect of dronabinol was sustained for up to five months at dosages ranging from 2.5 mg to 20 mg per day.
Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Concentrations of both parent drug and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing and decline over several days.
The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day) have been studied in healthy subjects.
Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Subjects (n=34; 20-45 years) under Fasted Conditions:
| Mean (SD) PK Parameter Values | |||
|---|---|---|---|
| Twice Daily Dose | Cmax ng/mL | Median Tmax (range), hr | AUC(0-12) ng•hr/mL |
| 2.5 mg | 1.32 (0.62) | 1.00 (0.50-4.00) | 2.88 (1.57) |
| 5 mg | 2.96 (1.81) | 2.50 (0.50-4.00) | 6.16 (1.85) |
| 10 mg | 7.88 (4.54) | 1.50 (0.50-3.50) | 15.2 (5.52) |
Cmax: maximum observed plasma concentration; Tmax: time to maximum observed plasma concentration; AUC(0-12): area under the plasma concentration-time curve from 0 to 12 hours.
A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was observed with increasing dose over the dose range studied.
In a published study, the effect of food on the pharmacokinetics of dronabinol was studied by concomitant dosing of dronabinol with a high-fat (59 grams of fat, approximately 50% of total caloric content of the meal), high calorie meal (approximately 950 calories). An appreciable food effect was observed, resulting in a 4-hour delay in mean Tmax and 2.9-fold increase in total exposure (AUCinf), but Cmax was not significantly changed.
Dronabinol has an apparent volume of distribution of approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%.
The pharmacokinetics of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.
Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-hydroxy-delta-9-THC, are present in approximately equal concentrations in plasma. Published in vitro data indicates that CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of dronabinol. CYP2C9 appears to be the enzyme responsible for the formation of the primary active metabolite.
Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.
Due to its re-distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time. Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.
In a study of dronabinol involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.
Formal drug-drug interaction studies have not been conducted with dronabinol.
The enzyme inhibition and induction potential of dronabinol and its active metabolite are not completely understood.
Published data showed an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol.
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