Disposition, bioavailability, and serum protein binding of pentachlorophenol in the B6C3F1 mouse.

The toxicokinetics of pentachlorophenol (PCP) were studied in B6C3F1 mice, a strain in which PCP was previously found to be carcinogenic. In a crossover design, doses of 15 mg/kg were given intravenously (bolus) and orally (gastric intubation) to six animals. Concentrations of PCP in blood, urine, and feces were measured by capillary gas chromatography with electron-capture detection. After intravenous administration, the values of clearance and volume of distribution were 0.057 +/- 0.007 L/hr/kg and 0.43 +/- 0.06 L/kg, respectively. These two parameters exhibited low intermouse variability (coefficients of variation less than 14%). The elimination half-life was 5.2 +/- 0.6 hr. After oral administration, the PCP peak plasma concentration (28 +/- 7 micrograms/ml) occurred at 1.5 +/- 0.5 hr and absorption was complete (bioavailability = 1.06 +/- 0.09). The elimination half-life was 5.8 +/- 0.6 hr. Only 8% of the PCP dose was excreted unchanged by the kidney. PCP was primarily recovered in urine as conjugates. A portion of the dose was recovered in urine as the mutagen, tetrachlorohydroquinone (5%) (TCHQ), and its conjugates (15%). For both PCP and TCHQ, sulfates accounted for 90% or more of the total conjugates (glucuronides and sulfates).

Colon-specific delivery of dexamethasone from a glucoside prodrug in the guinea pig.

Dexamethasone-beta-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent, dexamethasone. The ability of this prodrug to deliver dexamethasone selectively to the colon depends not only on its being slowly absorbed from the alimentary canal, but also on its having chemical and enzymatic stability in the stomach and small intestine. Once reaching the large bowel, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-beta-D-glucoside for colon-specific delivery of dexamethasone is assessed by determining the rates of its hydrolysis down the alimentary canal of the guinea pig, an animal in which an inflammatory bowel disease model has been developed. The hydrolytic activity is examined in tissues and luminal contents of the stomach, proximal and distal segments of the small intestine, cecum, and colon. For the tissues, the greatest hydrolytic activity is in the proximal small intestine, while the stomach, cecum, and colon have only moderate activity. In contrast, the contents of the cecum and colon show greater activity than the contents of the small intestine and stomach. The luminal contents retained beta-glucosidase activity even after repeated centrifugation and resuspension in a buffer. The activity was unaffected by homogenization. These observations suggest that hydrolytic activity is associated with enzymes located on the surface of luminal cells. The movement and hydrolysis of dexamethasone-beta-D-glucoside down the gastrointestinal tract of the guinea pig are also examined. About 20 to 30% of an oral dose appears to reach the cecum. Here the prodrug is rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-beta-D-glucoside is poorly absorbed in the gastrointestinal tract (bioavailability, less than 1%). There is a ninefold selective advantage for delivery of dexamethasone in cecal tissues in the guinea pig under the conditions of this experiment. Thus, there is a potential for a decrease in the usual dose and a concomitant reduction in the systemic exposure to dexamethasone. Because humans have much less glucosidase activity in the small intestine, even greater site-selective delivery to the cecum and colon is expected.

Simultaneous assay of pentachlorophenol and its metabolite, tetrachlorohydroquinone, by gas chromatography without derivatization.

A sensitive capillary gas chromatographic method was developed for the simultaneous determination of pentachlorophenol and its major metabolite, tetrachlorohydroquinone, in plasma, urine and feces. The method involved a simple one-step liquid-liquid extraction with diethyl ether and electron-capture detection gas chromatography on a fused-silica capillary column coated with 50% methylsilicone-50% trifluoropropylsilicone. The detection limit of both compounds was 50 ng/ml in plasma (from an initial volume of 0.1 ml), 100 ng/ml in urine and 100 ng/g in feces. Optimal conditions for both chemical and enzymatic hydrolysis were defined to measure conjugates of both pentachlorophenol and tetrachlorohydroquinone in urine. Tetrachlorohydroquinone was found to be unstable in plasma and urine; means to prevent its degradation during sample collection and storage by addition of ascorbic acid and ethylenediaminetetracetic acid are presented. This chromatographic method was shown to be precise, accurate and specific. It was successfully applied to toxicokinetic studies in rat.

Pharmacokinetics of nitroglycerin and its dinitrate metabolites over a thirtyfold range of oral doses.

The pharmacokinetics of nitroglycerin and the formation of its dinitrate metabolites (1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate) were determined in six healthy volunteers after administration of six oral solution doses ranging from 0.4 mg to 13 mg. ANOVA analysis indicated significant differences between subjects for all Cmax/dose and AUC/dose measurements. No significant difference between doses were noted for these parameters except for AUC/dose for 1,3-glyceryl dinitrate. The ratio of metabolites (1,2-metabolite/1,3-metabolite) for the 0.4 mg dose was significantly different from the ratios for the doses of 1.6 mg or higher. Measurements of the combined residence time parameter suggest nonlinearity in nitroglycerin absorption and metabolism processes of AUMC/AUC between the 0.4 and the 13 mg doses. Consistent results were observed in the AUC ratios of metabolites for 0.4 mg doses of nitroglycerin between oral and sublingual administrations, suggesting that the increased metabolite ratio noted for sublingual nitroglycerin may reflect differences in dose, rather than differences in route of administration.

Simultaneous determination of nitroglycerin and its dinitrate metabolites by capillary gas chromatography with electron-capture detection.

A sensitive gas chromatographic-electron-capture detection method for the simultaneous determination of the antianginal drug nitroglycerin (GTN) and its dinitrate metabolites (1,2-GDN and 1,3-GDN) was developed. Human plasma samples (1 ml) spiked with 2,6-dinitrotoluene as the internal standard were extracted once with 10 ml of a methylene chloride-pentane mixture (3:7, v/v). Using this solvent system, less contaminants are extracted into the organic phase from plasma, resulting in cleaner chromatograms and prolonged column life. A break point was observed on the standard curves of GTN and GDNs. The two linear regions for the detectable concentrations of GTN are 0.025-0.3 and 0.3-3 ng/ml and for 1,2-GDN and 1,3-GDN they are 0.1-1 and 1-10 ng/ml. The limits of detection by this method for GTN, 1,2-GDN and 1,3-GDN in plasma are 0.025, 0.1 and 0.1 ng/ml, respectively.

Lack of effect of diazepam on methadone metabolism in methadone-maintained addicts.

Four methadone-maintained subjects were given diazepam (0.3 mg/kg) for 9 days. During the dual drug period, the effects and kinetics of methadone and of its major pyrrolidine metabolite were not altered. These findings indicate that, unlike its effects in rodents, diazepam does not inhibit the metabolism of methadone in man.

Gas chromatographic analysis of meperidine and normeperidine: determination in blood after a single dose of meperidine.

A method is described for the determination of meperidine and its pharmacologically active metabolite, normeperidine, in blood, plasma, and urine using gas chromatography with nitrogen-phosphorus detection. Structural analogs of both meperidine and normeperidine were used as internal standards. Unlike previously reported assays, this procedure was sensitive and convenient enough for use in pharmacokinetic studies of both meperidine and normeperidine following single doses of meperidine. The assay was sensitive to 5 ng of meperidine/ml and 2.5 ng of normeperidine/ml extracted from a 1-ml biological sample. The between-assay coefficients of variation at these concentrations were 9.4 and 10.4%, respectively.

Determination of methadone and its primary metabolite in biologic fluids using gas chromatography with nitrogen-phosphorus detection.

A method is described for the determination of methadone and its primary metabolite, 1,5-dimethyl-3,3-diphenyl-2-ethylidinepyrrolidine, in biologic fluids using gas chromatography with nitrogen-phosphorus detection. A simple extraction scheme is employed that is convenient for processing the large numbers of samples generated in pharmacokinetic studies. The method is sensitive enough for accurate determination of concentrations less than 5 ng/mL of both methadone and its primary metabolite in 1 mL of biologic specimens.

Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects.

Plasma concentrations and urinary excretion of meperidine and its metabolite normeperidine were determined after intravenous and oral administration to 11 men; five men had hepatic cirrhosis and six were normal. Systemic clearance of meperidine was smaller and bioavailability and half-life greater in the cirrhotic patients than in the normal subjects. Plasma concentrations and 24-hr urinary excretion of normeperidine was lower and persistence of normeperidine in plasma longer in the patients with cirrhosis. The route of administration did not alter the fraction of normeperidine generated from meperidine. The results suggest that in patients requiring repeated meperidine dosage the drug should be taken parenterally rather than orally to allow maximal analgesia and minimal formation of normeperidine. Patients with cirrhosis may be relatively protected from normeperidine toxicity because of impaired formation, but the risk of cumulative toxicity may be greater than in normal subjects because of slower elimination of the metabolite and greater sensitivity to the effects of narcotics on the central nervous system.