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The bioavailability of delta-9-tetrahydrocannabinol (delta 9-THC) from suppository formulations containing several polar esters was studied. The esters tested were the hemisuccinate, N-formyl alaninate, N-methyl carbamate, and methoxy acetate. These esters were administered to monkeys in both lipophilic and hydrophilic suppository bases, namely, Witepsol H15 and polyethylene glycol, respectively. Each suppository contained a dose equivalent to 10 mg delta 9-THC. Blood samples were analyzed for both delta 9-THC and its carboxylic acid metabolite (ll-nor-delta 9-THC-9-COOH) using gas chromatography/mass spectrometry. The data showed that, with the exception of the hemisuccinate, no delta 9-THC or its metabolite was detected in the blood samples using the Witepsol H15. Using polyethylene glycol, low levels of delta 9-THC and its metabolite were detected in blood for all esters tested. The levels, however, were lower than those observed with delta 9-THC hemisuccinate using Witepsol H15. Subsequent studies in the conscious dog using the hemisuccinate in Witepsol H15 showed 67% bioavailability of delta 9-THC with a linear response in the dose range equivalent to 5-20 mg of delta 9-THC. No significant bioavailability differences were found when delta 9-THC hemisuccinate ester was administered in various lipophilic bases (Hydrokote 25, Kaomel, Suppocire AIML, and Witepsol H15).

Oral administration of delta-9-tetrahydrocannabinal (delta 9-THC) was shown to result in low and erratic bioavailability, while the drug showed no bioavailability from various suppository formulations. delta 9-THC-Hemisuccinate was formulated as a prodrug for delta 9-THC in suppositories using Witepsol H15 base. The bioavailability of delta 9-THC from this formulation was evaluated in monkeys. The plasma levels of delta 9-THC and its metabolite 11-nor-delta 9-THC-9-COOH were determined using GC/MS analysis. The calculated bioavailability of delta 9-THC from this formulation was found to be 13.5%. Non-compartmental analysis of the plasma concentration data using statistical moments showed the mean residence time (MRT) for delta 9-THC in the body to be 3 h following iv administration of delta 9-THC or its hemisuccinate ester (3.4 and 2.7 h, respectively), as compared with 5.8 h following rectal administration of the delta 9-THC hemisuccinate. The observed rectal bioavailability of delta 9-THC from suppositories containing the hemisuccinate ester as a prodrug is of significant importance in developing an alternative approach to oral administration of the drug.

Tritium-labeled 3-n-pentadecylcatechol and its diacetate ester were fed to Sprague-Dawley rats. Both compounds were dissolved in ethanol and in corn oil vehicles and administered by gavage. The rats were placed in metabolic cages, and the urine and feces was determined by liquid scintillation counting, and the percentage of the administered dose was utilized as a measure of absorption. While there was no difference between the absorption of either compound, absorption was affected by the vehicle. Approximately 30% of the administered radioactivity appeared in the urine when ethanol was the vehicle, but about half that amount (14%) was excreted in the urine when the compounds were dissolved in corn oil. A subsequent bile cannulation study showed that the balance of the radioactivity found in the feces was not a result of biliary excretion. The majority of the activity recovered from urine and feces was eliminated within 48 hr after dosing. These data indicate that oil is a poor vehicle for GI absorption of urushiol components.

Commercially available 250-mg penicillamine tablets were converted into enteric-coated tablets. Based on in vitro dissolution and disintegration tests, tablets coated with five layers of a cellulose acetate phthalate formulation by a modified pan coating technique were judged to be superior to other coated tablets. These tablets resisted disintegration in simulated gastric fluid over a 4-h period and disintegrated in an average of 21 min in simulated intestinal fluid. Enteric-coated penicillamine tablets were tested in vivo in nine weanling pigs divided into three groups: a negative control group, a test group dosed with enteric-coated penicillamine tablets, and a positive control group dosed with uncoated tablets. The incidence of GI tract bleeding, as determined by daily occult blood tests of the stools, was significantly less in the animals receiving the enteric-coated tablets when compared with the positive control group. The enteric-coated dosage form appeared to decrease GI tract irritation caused by penicillamine. Plasma concentration-time curves for penicillamine in the pigs were similar in shape to those reported in humans. Atypical double peaks occur in both species. Relative bioavailability of the enteric-coated tablet was found to be 67% when compared with the uncoated tablet. This apparent reduction is probably due to a large intrasubject variation in areas under the plasma concentration-time curves and not to a dosage form effect.

Thirty-two different cannabinoids were tested for their ability to reduce intraocular pressure (IOP) in the rabbit. These included many of delta 9- and delta 8-THC derivatives and metabolites along with other natural and synthetic cannabinoids. In addition, some non-cannabinoid constituents of Cannabis were screened using the same model. All compounds were administered intravenously, while only a few were tested topically in mineral oil. Water soluble derivatives of delta 9- and delta 8-THC were prepared and tested topically in aqueous solution. The data revealed that certain derivatives of delta 9-and delta 8-THC were more active in lowering IOP than the parent cannabinoids. In addition, compounds other than delta 9- and delta 8-THC and their derivatives were shown to have activity.

The described pharmacokinetic analysis involved two separate studies on nine dogs randomly assigned to three groups of three dogs each. In the first study, the effect of varying the dosage of tolazamide was examined. The second study concerned the effect of varying the dosage of oxyphenbutazone on tolazamide. A 3 x 3 Latin square was used to study both effects. Each group received each treatment, with a minimum of 1 week separating each session. THe pharmacokinetics of tolazamide followed a two-compartment open model. The hybrid rate constants, alpha and beta, were not significantly different at the three dosages when measured by a three-way analysis of variance. The only significant difference at the three dosage levels of tolazamide was in the apparent volume of distribution. In the pharmacokinetic interaction associated with intravenous administration of one dose of tolazamide and three doses of oxyphenbutazone, the apparent volume of distribution and the hybrid rate constant alpha did not change significantly while the hybrid rate constant for tolazamide, beta, seemed to decrease with increasing oxyphenbutazone.

Water soluble nonalkaloid fractions of Erythroxylon coca were screened in mice for their effects on oxygen utilization and central nervous system (CNS) activity. The fractions were screened in dogs for cardiovascular, blood glucose, and respiratory changes. No CNS effects were demonstrated in mice; however, there was a reduction in the oxygen utilization rate. Intravenous administration of the extract to dogs produced hyperglycemia, a reduction in heart rate, and a decrease in blood pressure. No substantial change in the respiratory rate and tidal or minute volumes were observed.

Carbon-14-labeled aflatoxin B1 was prepared by growing Aspergillus parasiticus in medium containing sucrose-14-C as the sole carbon source. The 14-C-labeled aflatoxin B1 was extracted with chloroform and purified by thin-layer chromatography (TLC) followed by precipitation from solution and washing. The 14-C-labeled aflatoxin B1 was intravenously given to anesthetized dwarf White Leghorn or Rhode Island Red hens with cannulated ureters and bile ducts. The 14-C had a calculated plasma half-life of 1.5 minutes and rapidly appeared in the bile. The 14-C concentration in the bile reached values approximately 7 times maximum for plasma, and most could no longer be extracted with chloroform. This finding indicated that metabolites of the 14-C-labeled aflatoxin B1 had been excreted against a concentration gradient into the bile. The quantities of 14-C excreted via bile, urine, and intestinal contents remained at a fairly constant ratio of 70:15:15, respectively, over the 315-minute experimental period. Six major chloroform-soluble compounds containing 14-C were isolated. Three of these were tentatively identified as aflatoxin B1, B2, and M1. A 4th was believed to be aflatoxin B2a. None of the early chloroform-soluble metabolites were as cytotoxic as aflatoxin B1.

Poison oak urushiol was compared with its esterified derivative for toxicity after oral administration to rats and guinea pigs. No hematological or pathological changes were noted and there were no differences seen in clinical chemistry measurements when compared to clinical biochemical and hematological reference values of normal experimental animals. Comparative LD50 studies in mice and tissue reactivity studies in rabbits indicated that acetylated urushiols were substantially less toxic than free urushiols. However, neither poison oak urushiol or poison oak urushiol acetate appeared to produce any tissue toxicity not related to a direct irritant effect. The free urushiol produced a much greater degree of skin irritation than did the urushiol acetate. Whether or not an animal had been sensitized to urushiol apparently had no effect on organ toxicity.

A technique of esophageal cannulation used in rats was adapted for use in the sub-human primate. Cannulation of the esophagus requires general surgical skills and a very short postoperative recovery period. No interference in eating habits or tendency toward vomiting was noted following cannulation. This technique allows the investigator an effective method for oral dosing of drugs with minimal physical and emotional stress to the animals and is quite appropriate for oral drug self-administration studies.

Serum progesterone levels from a vaginal tablet formulation and six different vaginal suppository formulations, each containing 25 mg of progesterone, were evaluated in mongrel dogs. Bioavailabilities relative to an intravenous dose of progesterone were calculated. The vaginal tablet was found to have a significantly higher bioavailability compared with the vaginal suppositories.