Mario Perez-Reyes

Metabolism, disposition, and kinetics of delta‐9‐tetrahydrocannabinol in men and women

A comparative study was done in women and men of the effects of Δ9‐tetrahydrocannabinol (Δ9‐THC), intravenously or orally, on dynamic activity, metabolism, excretion, and kinetics. In general no differences between the two sexes were observed. Δ9‐THC is converted by microsomal hydroxylation to 11‐hydroxy‐Δ9‐THC (11‐OH‐Δ9‐THC), which is both a key intermediate for further metabolism to 11‐nor‐Δ9‐THC‐9‐carboxylic acid (11‐nor‐acid) by liver alcohol‐dehydrogenase enzymes and a potent psychoactive metabolite. Major differences in the ratio of the concentration of 11‐OH‐Δ9‐THC to that of Δ9‐THC in plasma were found after intravenous dosing (ratio 1:10 to 20) compared with oral administration (ratio 0.5 to 1:1). The final metabolic products are the 11‐nor‐acids and the related, more polar acids. Urinary excretion of Δ9‐THC is restricted to acidic nonconjugated and conjugated metabolites. After 72 hr mean cumulative urinary excretion, noted for both routes and for both sexes, ranged from 13% to 17% of the total dose. After 72 hr the cumulative fecal excretion for both sexes after intravenous administration ranged from 25% to 30%; after oral administration the range was 48% to 53%. Metabolites were found in the feces in large concentration in the nonconjugated form; concentrations of 11‐OH‐Δ9‐THC were particularly noteworthy. Kinetics of Δ9‐THC and metabolites were much the same for female and male subjects. For Δ9‐THC, terminal‐phase t½s for both sexes, irrespective of the route, ranged from 25 to 36 hr. A comparison of the results for AU C i dose (Δ9‐THC) after oral dosing with comparable data from intravenous administration indicated bioavailability of the order of 10% to 20% for both sexes. After intravenous Δ9‐THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes).

A comparison of the pharmacological activity in man of intravenously administered 1368-11368-11368-1, cannabinol, and cannabidiol

Se hizo un estudio comparativo de la actividad delΔ 9-tetrahidrocannabinol, cannabinol, y cannabidiol en producir efectos similares a la marihuana cuando son inyectados i.v. a humanos. Estas substancias son los componentes predominantes de la marihuana o del hashish. Se encontro que a las dosis inyectados cannabidiol no tiene ninguna potencia, y que cannabinol es capaz de producir efectos tipicos de la marihuana, aunque a dosis varias veces mas grandes que las delΔ 9-tetrahidrocannabinol.

Free‐base cocaine smoking

Six healthy male, paid subjects smoked 50 mg of free‐base cocaine in a specially designed glass pipe under a rigidly controlled smoking protocol. The method of heating the pipe and the temperature that produced the most efficient and consistent vaporization of the drug had been determined experimentally. The psychological and cardiovascular effects of smoking free‐base cocaine were recorded. Approximately 26% of the original material was recovered from the pipe after smoking. Simulated smoking experiments in vitro indicated that only 44% of the material not trapped in the pipe was cocaine and that over 90% of this cocaine was delivered during the first four puffs (i.e., during the first 2 min of simulated smoking). These findings indicate that of the original 50 mg of cocaine free base placed in the pipes bowl, only 32% could have been inhaled (16.3 ± 0.6 mg). The cocaine free base inhaled induced psychological and cardiovascular effects similar to, or slightly more intense and pleasurable than, the effects of 20 mg of cocaine HCl (18 mg of cocaine base) taken intravenously by the same subjects and also induced a slightly more intense craving for another dose.

Comparison of effects of marihuana cigarettes of three different potencies

Marihuana cigarettes containing 1.32%, 1.97%, and 2.54% Δ9‐tetrahydrocannabinol (THC) were smoked by six experienced marihuana users at weekly intervals in a double‐blind cross‐over design under laboratory conditions. Puff duration, number of puffs taken, duration of inhalation holding, interval between puffs, and duration of smoking were recorded for each cigarette smoked. The portion of each cigarette remaining after smoking was weighed and analyzed to determine THC content. Subjective ratings of the “high” achieved and the heart rate acceleration induced by smoking the marihuana were measured. The plasma concentrations of THC and of its principal metabolite, 11‐nor‐Δ9‐THC‐9‐carboxylie acid (9‐carboxy THC), were determined by radioimmunoassay of blood samples drawn at frequent intervals for 6 hr. The results indicate that, irrespective of the potency of the marihuana, the pattern of smoking was much the same. The magnitude of the subjective high, heart rate acceleration, THC, and 9‐carboxy THC plasma concentrations were proportional to potency. This dose response was particularly clear between the 1.32% and the 2.54% cigarettes. Peak plasma concentrations of THC consistently occurred 7 to 8 min after initiation of smoking and declined thereafter despite continued smoking for another 6 to 10 min. Peak subjective high and peak heart rate acceleration occurred several minutes after the end of smoking and at a considerable interval after maximal THC plasma concentrations were reached.

The Metabolism of Δ9‐Tetrahydrocannabinol and Related Cannabinoids in Man

Abstract: The metabolism of Δ9‐tetrahydrocannabinol (THC) and related cannabinoids in man has been studied in detail utilizing intravenous, oral, and smoking routes of administration. The general pattern of metabolism was the same in all studies involving THC and related cannabinoids. Microsomal hydroxylation allylic to the Δ9‐THC double bond occurs, the major product resulting in formation of an 11‐CH2OH moiety; minor hydroxylation occurs on the C‐8 carbon. Nonmicrosomal oxidation of the resultant 11‐OH‐Δ9‐THC to 11‐nor‐Δ9‐THC‐9‐carboxylic acid and to other more polar acids generates the major terminal metabolic products. After oral administration, approximately equal quantities of THC and its highly active 11‐hydroxy metabolite were formed, whereasthe latter metabolite is a minor constituent after administration by intravenous or smoking routes. Initial pharmacokinetic analyses of the data show that the mean terminal‐phase (β‐phase) plasma half‐life after intravenous administration of THC was about 30 hours; after oral administration, it was 23 hours. No significant statistical difference was noted between men and women as to metabolic routes or plasma terminal‐phase half‐lives.

Intravenous Injection in Man of Δ9-Tetrahydrocannabinol and 11-OH-Δ9-Tetrahydrocannabinol

A microsuspension of Δ9-tetrahydrocannabinol and of its metabolic derivative 11-OH-Δ9-tetrahydrocannabinol has been prepared with 25 percent human serum albumin as the vehicle. Intravenous infusion of this preparation to humans indicates that both tetrahydrocannabinols are equally potent in producing the typical marihuana-like pschological and physiological effects.

Pharmacology of orally administered Δ9‐tetrahydrocannabinol

A systematic study of the oral administration of 35 mg. of Δ9‐tetrahydrocannabinol (Δ9‐THC) in 5 different vehicles indicates that the speed and degree of absorption are greatly influenced by the vehicle. When the same vehicle was used, absorption of the drug varied significantly among individuals. The psychologic effects were characterized by a marihuana‐like “high” qualified by experienced sub;ects to be more intense than that associated with smoked marihuana or hashish. Predominant physiologic effects were congestion of the conjunctiva, tachycardia, and moderate increases in blood pressure. Hypotention with bradycardia occurred when the blood pressure control was challenged by a change in posture or blood volume. The biologic half‐life of the drug appears to be less than 48 hours. Thin‐layer chromatographic analysis indicates that the metabolites in the plasma are the 11‐OH‐Δ9‐THC, an unknown compound, the 8,11‐di‐OH‐Δ9‐THC, and a group of more polar substances located at the origin. Δ9‐THC and its metabolites are excreted extensively in the urine and feces. The maior urinary metabolites are the 8,1l‐di‐OH‐Δ9‐THC and polar substances where cannabinoid acids predominate. Appreciable amounts of Δ9‐THC are found in feces.

Relationship between plasma delta-9-tetrahydrocannabinol concentration and pharmacologic effects in man

The relationship between each of two pharmacologic effects (tachycardia and psychological “high”) of delta-9-tetrahydrocannabinol (THC) and plasma THC concentration was investigated in three male and three female experienced marihuana smokers. Each subject smoked one 1% THC cigarette on two occasions separated by 2 h. Heart rate and subjective psychological self-rating were determined frequently throughout the 4 h study period. Data were analyzed by calculating the area under the parameter versus time curves, constructing hysteresis plots, and calculating the decay rate constants from pharmacologic effect versus time plots. In both males and females, dose inhaled and psychological response were apparently equivalent for the first and second cigarettes. While all subjects exhibited marked tachycardia in response to the first cigarette, heart rate in both male and female subjects was not increased as markedly during the second cigarette. Interestingly, female subjects had less tachycardiac response than males during the second cigarette. Hysteresis plots revealed that both heart rate and subjective psychological effects were elicited in an effect compartment which was “deep” relative to the reference plasma compartment. The time courses of tachycardiac and psychological responses lagged behind the plasma THC concentration-time profile. Zero-order decay rate constants for subjective psychological rating did not change substantially from the first to second cigarette. This study suggests that plasma THC concentration is a poor predictor of simultaneously occurring physiological and psychological pharmacologic effects.

Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine

Cocaethylene (the ethyl ester of benzoylecgonine) is a product of the interaction between ethanol and cocaine. The results of preclinical studies and of a pilot clinical study have shown cocaethylene to produce pharmacologic effects similar to those of cocaine. However, no information is available concerning the potency and pharmacokinetics of cocaethylene in comparison to those of cocaine in humans. We report the results of a single-blind, crossover study in which six male, healthy, paid volunteers, who were moderate users of cocaine, were intravenously injected with the water soluble fumarate salt of cocaethylene (0.25 mg/kg cocaethylene base) or an equivalent dose of the water soluble hydrochloride salt of cocaine (0.25 mg/kg cocaine base). Each dose was dissolved in normal saline and injected over a 1-min interval. Test sessions were separated by a 1-week interval. The variables measured were: cocaine and cocaethylene plasma concentrations, subjective and cardiovascular effects. The results indicate, that in comparison to cocaine, cocaethylene had a significant smaller elimination rate constant (0.42 versus 0.67 l/h), had a longer elimination half-life (1.68 versus 1.07 h), and induced ratings of “high” and changes in heart rate that were of lower magnitude (65%, and 43%, respectively). During the period of time that pharmacologic effects were present the plasma concentrations of cocaine and cocaethylene were statistically indistinguishable. This finding supports the conclusion that in humans cocaethylene is less potent than cocaine.

Phencyclidine disposition after intravenous and oral doses

[3H]‐Phencyclidine (PCP) hydrochloride was given in intravenous (0.1 or 1 mg) or oral (1 mg) doses to male subjects. After 1 mg IV, drug and metabolites were recovered in urine (72.8 ± 4.0% of dose), feces (4.7 ± 0.9%), and perspiration. Fecal excretion was low (3.4 ± 0.4%) after oral dosing and oral bioavailability was estimated at 72%. PCP comprised 16% of urinary radioactivity with 31% consisting of enzymatically hydrolyzable conjugates of hydroxylated metabolites. Both cis and trans isomers of 4‐phenyl‐4‐(1‐piperidinyl)cyclohexanol were found. Maximum average plasma PCP concentrations of 2.7 to 2.9 ng/ml were observed after oral and intravenous 1‐mg doses. Blood/plasma ratios were approximately 1.0 and plasma binding was about 65%. Parent drug was found in saliva. Apparent terminal phase half‐lifes averaged 21 ± 3 hr (harmonic mean 17 hr, range 7 to 46 hr). The volume of distribution averaged 6.2 ± 0.3 l/kg. Renal clearances were variable, but the average was 9% of the total clearance. Thus, PCP is cleared principally by metabolism.