Activity of delta8- and delta9-tetrahydrocannabinol and related compounds in the mouse.

The 11-hydroxy metabolites of Delta(8).- and Delta(9)-tetrahydrocannabinol are more active than the parent compounds when administered to mice by either the intravenous or intracerebral route. Both Delta(8)- and Delta(9)-tetrahydrocannabinol are rapidly and extensively metabolized by the liver and not by the brain. The hypothesis that the 11-hydroxy metabolites may be the active form of tetrahydrocannabinol is discussed

Phencyclidine and phenylcyclohexene disposition after smoking phencyclidine.

Five men who smoked parsley cigarettes containing 100 micrograms of [3H]-phencyclidine hydrochloride (PCP.HCl) inhaled 69 +/- 5(SEM) % of the total radioactivity in the cigarette. Both PCP and its pyrolysis product, 1-phenylcyclohexene (PC), were found and measured in plasma. Calculations based on the assumption that the ratio of these two products was the same as in simulated smoking studies and based on either area under the curve or urinary excretion of PCP indicated that most of the PCP in smoke was absorbed. Mean half-life (t1/2) of PCP (24 +/- 7 hr, harmonic mean 18 hr) and ratios of metabolites in plasma and urine were close to those previously reported after intravenous and oral doses. A second peak in PCP plasma concentrations was observed, possible due to show efflux from the lungs. PC plasma concentrations (maximum 0.35 +/- 0.06 pmol/ml) were lower than those of PCP (maximum 0.62 +/- 0.09 pmol/ml) and its mean t1/2 (14 +/- 3 hr, harmonic mean 12 h) was shorter than that of PCP. Only traces of PC were found in urine. Only small amounts of metabolites from PC were found nonconjugated in plasma (to about 0.1 pmol/ml) or urine (less than 2% of radioactivity), but larger quantities were found as enzyme-hydrolyzable conjugates in urine (6% of radioactivity). Conjugates were also found in plasma (to about 0.12 pmol/ml).

Urine pH and phencyclidine excretion.

Subeffective doses (0.5 mg) of 3H-phencyclidine (PCP) were given intravenously to three healthy men under two regimens designed to alkalinize or acidify their urine (oral sodium bicarbonate or ammonium chloride). The concentrations of PCP and its metabolites in saliva, plasma, and urine for 7 hr after injection were determined by high-performance liquid radiochromatography. A sample of perspiration from one subject was analyzed. The effects of physical exercise on the plasma concentration and urinary excretion of PCP were also studied. Multiple linear regression analysis showed the logarithm of renal clearance the renal clearance of PCP. PCP and its metabolites are also excreted in perspiration. Our results support clinical reports of the importance of vigorous acidification of urine and diuresis in treatment of PCP intoxication.

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.

Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats.

Bisphenol A (BPA) was evaluated at concentrations of 0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm ( approximately 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg/day of BPA) administered in the diet ad libitum to 30 CD((R)) Sprague-Dawley rats/sex/dose for 3 offspring generations, 1 litter/generation, through F3 adults. Adult systemic toxicity at 750 and 7500 ppm in all generations included: reduced body weights and body weight gains, reduced absolute and increased relative weanling and adult organ weights (liver, kidneys, adrenals, spleen, pituitary, and brain), and female slight/mild renal and hepatic pathology at 7500 ppm. Reproductive organ histopathology and function were unaffected. Ovarian weights as well as total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD). Mating, fertility, gestational indices; ovarian primordial follicle counts; estrous cyclicity; precoital interval; gestational length; offspring sex ratios; postnatal survival; nipple/areolae retention in preweanling males; epididymal sperm number, motility, morphology; daily sperm production (DSP), and efficiency of DSP were all unaffected. At 7500 ppm, vaginal patency (VP) and preputial separation (PPS) were delayed in F1, F2, and F3 offspring, associated with reduced body weights. Anogenital distance (AGD) on PND 0 was unaffected for F2 and F3 males and F3 females (F2 female AGD was increased at some doses, not at 7500 ppm, and was considered not biologically or toxicologically relevant). Adult systemic no observed adverse effect level (NOAEL) = 75 ppm (5 mg/kg/day); reproductive and postnatal NOAELs = 750 ppm (50 mg/kg/day). There were no treatment-related effects in the low-dose region (0.001-5 mg/kg/day) on any parameters and no evidence of nonmonotonic dose-response curves across generations for either sex. BPA should not be considered a selective reproductive toxicant, based on the results of this study.

Pyrolysis products of heroin.

Heating of heroin hydrochloride or of heroin at 250 degrees C led to extensive degradation. Major components of the pyrolysate were identified as heroin, 6-acetylmorphine, N,6-diacetylnormorphine, and N-acetylnorheroin by comparison of mass spectra and 13C- and 1H-nuclear magnetic resonance (NMR) spectra with those of authentic compounds. There was evidence for degradation of the piperidino moiety and the structure 3,4-diacetoxyphenanthrene was proposed for a minor product.

Analytical methods for quantitative and qualitative analysis of naltrexone and metabolites in biological fluids.

Analytical procedures for the determination of naltrexone and metabolites have been presented. The basic procedure involves the use of radiolabeled drugs and thin layer chromatography. Naltrexone, 6 beta-naltrexol and 2-hydroxy-3-O-methyl-6 beta-naltrexol were found by both the TLC procedure and combined gas chromatography-mass spectrometry. The presence of 3-O-methyl-6 beta-naltrexol was indicated by the TLC method, but this metabolite could not be found by mass spectrometry.

Pancreaticobiliary carcinoma associated with a large choledochal cyst: role of MRI and MR cholangiopancreatography in diagnosis and preoperative assessment.

The role of magnetic resonance (MR) imaging and MR cholangiopancreatography is demonstrated in a case of pancreaticobiliary carcinoma associated with a large choledochal cyst. The size of the cyst presented considerable difficulty in evaluation with both endoscopic retrograde cholangiopancreatography and computed tomography.

Metabolism and disposition of naltrexone in man after oral and intravenous administration.

The metabolism and elimination of [15, 16,-3H2]naltrexone was studied in man after oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and conjugated and unconjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely absorbed after oral administration. After oral and intravenous administration of naltrexone, about 60% of the dose was recovered in the urine in 48 and 72 hr, respectively. The route of administration did not significantly affect urinary clearance values obtained for unconjugated or conjugated naltrexone and 6 beta-naltrexol. The route of administration significantly affected terminal plasma half-life values obtained for unconjugated naltrexone (2.7 hr, iv; 8.9 hr, oral), but had little effect on comparable values obtained for total drug, conjugated naltrexone, and unconjugated and conjugated 6 beta-naltrexol. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol, and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine.

The metabolism of naltrexone in man.

The metabolism and elimination of [15,16-3H2] naltrexone hydrochloride was studied in man following oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and nonconjugated and conjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely in minor quantities. Naltrexone was almost completely absorbed following in the urine and only 5% in the feces. A similar urinary excretion pattern was observed after intravenous administration of naltrexone. In early time periods after oral administration there was a rapid increase in free naltrexone plasma levels up to 1 hr and then gradually declined. A similar pattern was observed for conjugated naltrexone and nonconjugated and conjugated 6 beta-naltrexol. These metabolites were found at levels 4-6 times higher than the parent compound at all times sampled. After intravenous administration, nonconjugated naltrexone plasma levels dropped sharply and continuously. The major metabolites exhibited a pattern closely resembling that found for oral administration. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine. The structure of the latter was rigorously proven by 13C-NMR. No evidence for the presence of noroxymorphone or 3-O-methyl-6 beta-naltrexol could be obtained by gas chromatography-mass spectrometry. The metabolism of naltrexone administered subcutaneously was also determined in two subjects. Larger amounts of 2-hydroxy-3-O-methyl-6 beta-naltrexol were found in plasma than had been present after oral or intravenous administration.

Identification of in vitro rat metabolites of 1-phenylcyclohexene.

In vitro metabolites of 1-phenylcyclohexene produced by the 10,000g supernatant fraction from rat liver homogenates were identified by a combination of spectrometric, chromatographic, and synthetic techniques. Initial oxidation occurred in the 3-position of 1-phenylcyclohexene to yield 1-phenyl-1-cyclohexen-3-one and 1-phenyl-1-cyclohexen-3-ol. Further allylic oxidation at the 6-position occurred to form 1-phenyl-6-hydroxy-1-cyclohexen-3-one and 1-phenyl-1-cyclohexene-3,6-diol. Trans-1-phenyl-1-cyclohexene-3,4-diol was also found and may have resulted from hydroxylation of 1-phenyl-1-cyclohexen-3-one alpha to the carbonyl to yield 4-hydroxy-1-phenyl-1-cyclohexen-3-one (not isolated) followed by carbonyl reduction. Oxidation of the double bond also occurred to give the cis and trans isomers of 1-phenylcyclohexane-1,2-diol as well as a compound postulated to be 1-phenylcyclohexane-1,2,3-triol.

Phencyclidine disposition in humans after small doses of radiolabeled drug.

Administration of small doses of radiolabeled phencyclidine hydrochloride (PCP X HCl) to normal volunteers has resulted in basic information on the disposition of PCP in humans. The drug and its metabolites were excreted mainly in the urine whether it was given orally or i.v. (73 +/- 4% of dose was recovered in urine after i.v. administration of 1 mg), with very little fecal excretion (3-5%) and some excretion in sweat. Oral bioavailability was 72 +/- 8%. Major metabolic pathways found involved hydroxylation of the cyclohexane and piperidine rings followed by conjugation. Oxidation to an aminopentanoic acid also occurred. PCP and phenylcyclohexene were inhaled when PCP was smoked. For PCP the weighted mean apparent terminal rate constant (beta) was 0.0395 +/- 0.0008 h-1 for 16 subjects, equivalent to a half-life of 17.6 h, but 2 subjects had half-lives of over 2 days. The volume of distribution (Vd, beta) was 6.2 +/- 0.3 liters/kg. At usual urinary pH, PCP excretion represented less than 10% of total clearance, but marked lowering of urinary pH can significantly increase the contribution of renal clearance to overall clearance.

Comparison of gas chromatography mass spectrometry methods for the determination of delta9-tetrahydrocannabinol in plasma.

A method for the identification of delta9-tetrahydrocannabinol by gas chromatography mass spectrometry has been developed, and this method has been compared with other techniques, such as detection via thin-layer chromatography using tritium labeled delta9-tetrahydrocannibinol and a dual gas chromatographic method. The gas chromatographic mass spectrometric method was found to be equal or superior to other techniques and has the added advantage of being highly specific for the compound analyzed. An alternate approach using chemical ionization is also described; however, this procedure does not show significant advantages over the electron impact method. These methods show a practical lower detection limit of 500 pg ml-1 of plasma in clinical practice.

Analytical methods for the determination of cannabinoids in biological media.

A pharmacokinetic study of the blood plasma levels in man of delta9-tetrahydrocannabinol, 11-hydroxy-delta9-tetrahydrocannabinol and cannabinol has been carried out by means of combined gas chromatographic-mass spectral analysis. In some cases comparison of the data was obtained on the same sample using thin layer chromatography of radiolabeled samples and electron capture gas-liquid chromatography. For the mass spectral studies appropriately deuterium labeled analogs of the previously named compounds were used both as internal standards and as a carrier for the relatively small amounts of nonlabeled drug present in plasma. Blood samples were obtainted at periodic intervals up to 24 hours from volunteers receiving 4-5 mg delta9-THC intravenously. After extraction and "clean-up" by Sephadex chromatography, the extracts were concentrated and subjected to glc-ms in the electron impact (ei) mode or alternatively with a chemical ionization (ci) source, in which case preliminary chromatography could be omitted. In all cases calibration curves were obtained from replicate analyses of spiked plasma containing the internal standard and various quantities of the cannabinoid under analysis. A typical biphasic elimination of the drug was observed with rapid elimination of delta9-THC from the blood over a period of 40 min followed by a much slower elimination up to 24 hours. The experimental data show that 11-hydroxy-delta9-THC is found in the plasma in quantities only about one-twentieth to one-twenty-fifth the values found for delta9-THC. Cannabinol was not found in significant quantities. Good agreement was obtained between the mass spectral analyses and the thin layer chromatography or electron capture gas-liquid chromatographic procedures.

Naltrexone disposition in man after subcutaneous administration.

The metabolism, excretion, and pharmacokinetics of [15,16-3H2]naltrexone were studied in six human males after sc administration of the hydrochloride salt. Biological fluids were analyzed by a combination of high performance liquid chromatography with liquid scintillation measurement of radioactivity. After administration, naltrexone was rapidly absorbed into the systemic circulation. The mean absorption rate constant was 0.091 +/- 0.008 min-1 (half-life of 7.6 min). In general the metabolic, excretory, and pharmacokinetic patterns for naltrexone were similar to those observed after iv administration of naltrexone to man. The terminal phase plasma rate constant was 0.413 +/- 0.035 hr-1 (half-life of 1.68 hr) for parent drug and 0.0786 +/- 0.0090 hr-1 (half-life of 8.8 hr) for the major metabolite, 6 beta-naltrexone. An average of 76 +/- 6% (+/- SD) of the total radioactivity was recovered in the urine within 72 hr after administration. Naltrexone was found in the urine in both the free (3.4 +/- 0.8% of dose) and conjugated (6.8 +/- 2.1% of dose) form. 6 beta-Naltrexol was present in urine largely in the unconjugated form (28 +/- 7% of dose) but the conjugated form was also found (12 +/- 3% of dose).

Carbon-13 nuclear magnetic resonance identification of 2-hydroxy-3-O-methyl-6beta-naltrexol as a minor naltrexone metabolite.

A carbon-13 nuclear magnetic resonance comparison of synthetic and biological samples was used to identify unequivocally 2-hydroxy-3-O-methyl-6beta-naltrexol as a minor naltrexone metabolite in humans. This study points up the increasing usefulness of natural abundance carbon-13 nuclear magnetic resonance techniques in metabolism studies.

Isolation of symlandine from the roots of common comfrey (Symphytum officinale) using countercurrent chromatography.

Three pyrrolizidine alkaloids, symlandine, symphytine, and echimidine (1-3), were isolated from the roots of Symphytum officinale using a one-step countercurrent chromatography procedure. The structures of 1-3 were confirmed by several spectroscopic techniques including 2D NMR methods. This is the first description of the separation of symlandine (1) from its stereoisomer, symphytine (2).

Two-generation reproductive toxicity study of dietary tributyl phosphate in CD rats.

Tributyl phosphate (TBP) was tested for reproductive toxicity in rats. Thirty weanlings/sex (F0) were exposed to TBP in the diet ad libitum at 0, 200, 700, or 3000 ppm for 10 weeks and then randomly mated within groups for 3 weeks with continued exposure. F0 parents and 10 F1 weanlings/sex/dose were necropsied, and adult reproductive organs, urinary bladders (both sexes), kidneys (males), and livers (females) were evaluated histologically. Thirty F1 weanlings/sex/dose continued exposure for 11 weeks and were bred as described above. F1 parents and F2 weanlings, 10/sex/dose, were then necropsied as described above. Adult toxicity was observed in both sexes and generations at 700 and 3000 ppm; observations included reduced body weights, weight gain and feed consumption, urinary bladder epithelial hyperplasia (both sexes), renal pelvis epithelial hyperplasia only at 3000 ppm (male kidneys), and centrilobular hypertrophy (female livers). At 200 ppm, transient reductions in body weight were observed in F0 and F1 females, with urinary bladder epithelial hyperplasia in F0 males and females and in F1 males. There was no evidence of reproductive toxicity, of reproductive organ pathology, or of effects on gestation or lactation at any dose tested. Postnatal toxicity was evidenced by consistent reductions in F1 and F2 pup body weights at 3000 ppm and by occasional weight reductions in F2 litters at 700 ppm, and was associated with maternal toxicity observed at these doses and times. Under the conditions of this study, a NOAEL was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 3000 ppm and the NOAEL for postnatal toxicity was approximately 200 ppm.