The concentration of caffeine in the blood and semen of men was measured after an oral dose of 200 or 400 mg caffeine. Caffeine was rapidly absorbed (mean tmax = 0.76 +/- 0.12 hour), with an average maximum concentration in the blood of 7.4 micrograms/ml for the 400-mg dose and 3.4 micrograms/ml for the 200-mg dose. The mean clearance of caffeine was 161 and 156 ml/min, while the mean volume of distribution was 50 and 47 liters for the 400- and 200-mg doses, respectively. Distribution of caffeine into the semen was rapid, with a concentration of caffeine in the semen almost identical to that observed concurrently in the blood (blood/semen concentration ratio = 0.97). The mean half-life of caffeine in the blood and semen was 3.7 and 3.6 hours, respectively, indicating that the decline of caffeine in the blood is very similar to that in semen. Thus, caffeine partitions rapidly into and out of the prostatic and seminal vesicular secretions, which contribute to the formation of the ejaculate.

Adult↗

PubMedDate not supplied

The secretion of methadone and its major metabolite in the gastric juice of humans: comparison with blood and salivary concentrations.

Four healthy subjects and four addicts on high daily maintenance doses of methadone each received a parenteral dose of methadone hydrochloride following an overnight fast. The concentration of methadone in blood was compared with that in the gastric juice obtained over 8 hr by continuous low-pressure suction via a nasogastric tube. The concentration in the gastric juice was 25-200 times that measured at the same time in the blood. Thus, 8 hr after the injection mean blood concentrations of 28 and 210 ng of methadone per ml were recorded in the normal subjects and the addicts, respectively. The corresponding concentrations in gastric juice were 2,200 ng/ml and 18,000 ng/ml, respectively. In the normal subjects about 2% of the administered dose was recovered in the gastric juice in 8 hr, whereas in addicts about 7% was recovered. The greater recovery of methadone from the addicts appears to be the result of the larger volume of gastric juice recovered from the latter subjects. Methadone was also excreted in the saliva of both groups of subjects. In addicts, salivary concentrations were often 10 times those recorded in the blood. The N-monodemethylated metabolite of methadone was identified in the gastric juice of addicts by gas chromatography and mass spectrometry.

Adult↗

PubMedDate not supplied

Identification of glucuronide metabolites of benzomorphan narcotic analgesic drugs in bile from the isolated perfused rat liver by gas chromatography and mass spectrometry.

The metabolism of four benzomorphan compounds was studied in the isolated perfused rat liver, and glucuronide metabolites were identified by combined gas chromatography-mass spectrometry (GC/MS). Cyclazocine, ketocyclazocine, volazocine, and pantazocine were each added to the perfusate of the isolated perfused rat liver and the bile collected for 3 hours. The residue from evaporation of the bile was derivatized with the dimethylsulfoxide anion and methyl iodide, and the permethylated glucuronide metabolites were identified by GC/MS. The four compounds were hydroxylated by the liver and excreted in the bile as phenolic glucuronides. For example, permethylated hydroxycyclazocine glucuronide had a mass spectrum with a molecular ion at m/e 533 and fragment ions at m/e 301 (aglycone), m/e 260 (loss of cyclopropyl group) and prominent ions at m/e 232, 201, 169, 141, and 101 caused by fragmentation of the permethylated glucuronic acid moiety. Perdeuteriomethylation demonstrated that pentazocine, volazocine, and cyclazocine were further metabolized by methylation of one hydroxy substituent and glucuronidation on the other. Pentazocine, cyclazocine, and ketocyclazocine were also metabolized to phenolic glucuronides of the parent drugs. N-deakylated metabolites of pentazocine, volazocine, and cyclazocine were identified both as permethylated glucuronic acid conjugates and as the trimethylsilyl derivatives of the aglycones, obtained by enzymatic hydrolysis on the conjugates in bile.

Analgesics, Opioid↗

PubMedDate not supplied

Inhibition and induction of theophylline metabolism by 8-methoxypsoralen. In vivo study in rats and humans.

The effects of 8-methoxypsoralen (8-MOP) on the metabolism of theophylline were studied in rats and humans. Rats were randomized into three groups and prepared with iv jugular catheters. Group I (N = 4) received a single ip injection of 27 mg/kg of 8-MOP, group II (N = 5) vehicle (corn oil), and group III (N = 4) 50 mg/kg/day of 8-MOP for 3 days. Rats were subsequently administered 15 mg/kg of theophylline iv, and timed blood samples (0.2 ml) were assayed for theophylline by HPLC. Theophylline clearance (ml/min/kg; mean +/- SD) was 1.7 +/- 0.3, 2.4 +/- 0.5, and 9.5 +/- 1.6 in groups I, II, and III, respectively. The half-life (harmonic mean) from 0.5 to 12 hr was 7.2, 3.6, and 0.8 hr. Urinary excretion of unchanged theophylline (mean +/- SD) from 0 to 24 hr was 60 +/- 10, 41 +/- 6, and 13 +/- 3% of the administered dose. In a crossover study, three healthy, male, nonsmokers received 600 mg of oral theophylline. Urine and plasma were collected for 48 hr. One week later, subjects received 1.2 mg/kg of oral 8-MOP followed in 1 hr by 600 mg of oral theophylline. Mean residence time of theophylline increased from 10.7, 17.2, and 12.2 hr in the control period, to 20.3, 19.0, and 18.4 hr after 8-MOP. The AUC (microgram.hr/ml) of theophylline increased from 204, 213, and 204, to 555, 364, and 432, while clearance (ml/min/kg) decreased from 0.74, 0.57 and 0.63, to 0.27, 0.33, and 0.30, respectively. Urinary excretion of unchanged theophylline from 0 to 48 hr increased from 14, 14, and 15, to 24, 21, and 20%. We conclude that 8-MOP administered acutely is a potent inhibitor of theophylline metabolism and chronically in the rat is a powerful inducer.

Animals↗

PubMedDate not supplied

Excretion of phenytoin into semen of rabbits and man. Comparison with plasma levels.

The concentration of phenytoin (diphenylhydantoin, DPH) was measured in plasma and semen of rabbits and man. In the rabbit, a single iv injection of DPH (4.64 mg) resulted in a concentration-time curve for DPH in semen parallel to the concentration-time curve for DPH in plasma (t1/2beta = 171 +/- 29 min). A semen/plasma drug concentration ratio of 0.20 was maintained for at least 8 hr, demonstrating that DPH concentrations in semen are directly proportional to DPH concentrations in plasma. In epileptic subjects maintained on oral DPH the mean drug concentration in semen was 2.31 microgram/ml while that in plasma was 13.8 microgram/ml. The mean semen-plasma DPH concentration ratio in man was 0.17; this closely approximates the observed ratio in rabbits.

Adult↗

PubMedDate not supplied

Disposition of 8-methoxypsoralen in the rat. Induction of metabolism in vivo and in vitro and identification of urinary metabolites by thermospray mass spectrometry.

The pharmacokinetics and metabolism of 8-methoxypsoralen (8-MOP) were measured in the catheterized rat after pretreatment for 3 days with phenobarbital (PB), beta-naphthoflavone (BNF), 8-MOP, or vehicle. After an iv injection of 10 mg/kg of [14C]8-MOP, timed blood samples were collected and analyzed using a sensitive and specific assay for [14C]8-MOP. Total body clearance of 8-MOP increased from 0.55 +/- 0.06 liter/kg/hr in control rats to 5.6 +/- 0.4, 2.7 +/- 0.4, and 1.2 +/- 0.0 liters/kg/hr in rats pretreated with BNF, PB, and 8-MOP, respectively, indicating that all three compounds are inducers of 8-MOP metabolism. The pattern of urinary metabolites was altered by the enzyme inducers. The urinary excretion of the sulfate conjugate of 5-hydroxy-8-methoxypsoralen was increased from 10 to 40% of the dose after pretreatment with PB. This intact conjugate was identified using thermospray and fast atom bombardment mass spectrometry. Pretreatment with 8-MOP and BNF increased 2- and 3-fold, respectively, the urinary excretion of a labile sulfate conjugate of 5,8-dihydroxypsoralen. Metabolism of 8-MOP was demonstrated in the 9000 g supernatant and microsomes of rat liver and shown to be inducible by pretreatment of rats with BNF, PB, and 8-MOP. 8-MOP was metabolized in incubations with liver microsomes at rates of 0.22 +/- 0.06, 0.38 +/- 0.06, 0.78 +/- 0.07, and 0.91 +/- 0.03 nmol/min/mg of protein for vehicle, 8-MOP-, PB-, and BNF-pretreated rats, respectively. Results of our investigation indicate that the success of therapy with 8-MOP may be influenced by pharmacokinetic interactions with other drugs.

Animals↗

PubMedDate not supplied

Characterization of glucuronide metabolites of carbamazepine in human urine by gas chromatography and mass spectrometry.

Glucuronide metabolites of carbamazepine (5 H-dibenz[b,f]azepine-5-carboxamide) were identified in human urine following chromatography on XAD-2 resin, permethylation, and combined gas chromatography and mass spectrometry with an SE-30 capillary column. Eight glucuronide metabolites, previously unidentified in man, were characterized as their permethylated derivatives. These included carbamazepine N-glucuronide (M+. 482), three isomers of dihydroxycarbamazepine O-glucuronide (M+. 542), three isomers of hydroxymethoxycarbamazepine O-glucuronide (M+. 542), and one isomer of hydroxycarbamazepine O-glucuronide (M+. 512). Other glucuronide metabolites, previously identified following enzymatic hydrolysis, were characterized as the unhydrolyzed, permethylated glucuronides, 10,11-dihydro-10,11-di--hydroxy carbamazepine O-glucuronide (M+. 544), and three isomers of monohydroxycarbamazepine O-glucuronide (M+. 512).

Biotransformation↗