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Biomedical subjects

A L Liu

Publications and source records attributed to A L Liu.

11 recordsLinked to original sources
PubMed1986

The metabolic disposition of 14C-ciramadol in humans.

Twelve subjects received single 15 mg oral doses of 14C-ciramadol. Excretion of the dose occurred almost entirely by the renal route (93.5 +/- 11.7 (S.D.)% of the dose), and only 0.7 +/- 0.6% of the dose was recovered in faeces indicating that absorption was essentially complete. More than 90% of the amount recovered in urine was excreted within 24 h after dosing. Unchanged drug accounted for 43.9 +/- 6.5% of the dose, while a phenolic glucuronide conjugate was the only major urinary metabolite accounting for a further 37.9 +/- 7.8%. A second glucuronide that was conjugated with the alicyclic ring was also identified but constituted only 2.3 +/- 0.6% of the dose. Concentrations of radioactivity in plasma reached a peak at 2 h after dosing and declined with a terminal disposition half life of 4.9 h. Only ciramadol and the aryl-O-glucuronide were detected in substantial amounts in plasma. Renal clearance of ciramadol amounted to 298 +/- 54 ml/min suggesting tubular secretion in addition to glomerular filtration.

Adult↗
PubMedDate not supplied

Excretion and stereoselective biotransformations of dl-, d- and l-norgestrel in women.

Excretion data and urinary metabolite patterns of di-, d-, and l-norgestrel were obtained from women who received a single, oral 1.5-mg dose of 14C-labeled racemic norgestrel (Ng) or one of its enantiomers. The average percentage of administered radioactivity +/- SD recovered in the urine after 7 days was 58.1 +/- 7.9% for dl-Ng, 44.8 +/- 8.9% for d-Ng, and 63.6 +/- 15.1% for l-Ng; in feces it was 23.4 +/- 7.7% (dl-Ng), 31.6 +/- 8.2% (d-Ng), and 24.8 +/- 10.7% (l-Ng). Different metabolite patterns were observed for each enantiomer in urine, and the pattern for the racemate appeared to be an approximate composite of the metabolite patterns of the two enantiomers. These differences in the metabolite pattern result from stereoselective transformations; notably 16 beta-hydroxylation of l-Ng and ring A reduction of d-Ng. Other stereoselective pathways noted were: 16 alpha- and 1 beta-hydroxylation as well as D-homoannulation of l-Ng and sulfate conjugation of l-16 beta-hydroxynorgestrel; 2 alpha-hydroxylation of d-Ng, formation of a labile neutral, polar compound which contained the norgestrel moiety in the d-form, and formation of a glucuronide of d-16 beta-hydroxynorgestre. The formation of phenolic derivatives occurred to a very minor degree from transformations of the biologically inactive l-enantiomer. With d-norgestrel, this formation occurred to an even lesser extent, if at all.

Adult↗
PubMedDate not supplied

Inhibition of ciramadol glucuronidation by benzodiazepines.

Studies on the inhibition of ciramadol glucuronidation by benzodiazepines were performed in vitro and in vivo. Ciramadol glucuronidation was slower (Vmax, 1.56 vs. 5.40 nmol/min/mg of microsomal protein) in human than in dog liver microsomes. Inhibition constants (Ki) for lorazepam and oxazepam were 3 to 4 times higher than that calculated for diazepam. Rates of morphine glucuronidation in human liver microsomes were assessed for comparative purposes and agreed with literature values. Each benzodiazepine appeared to be a competitive inhibitor of ciramadol and morphine UDP-glucuronyltransferase activity. The in vivo disposition of ciramadol was unchanged in dogs pretreated with lorazepam. After diazepam treatment no change in the Vdss of ciramadol occurred, but plasma clearance was significantly reduced, resulting in a prolongation of t1/2. Diazepam caused a significant reduction in the oral clearance of ciramadol, whereas no change occurred in systemic availability. Thus, diazepam may have had a secondary effect on hepatic blood flow (QH) and produced offsetting alterations in both intrinsic clearance (Cl int) and QH. A decrease in the area under the plasma concentration time curves of ciramadol aryl O-glucuronide following iv treatment with diazepam coupled with the in vitro data indicate that the mechanism for the decrease in the clearance of ciramadol is inhibition of its glucuronidation by diazepam. Since glucuronidation plays a major role in the elimination of ciramadol in man and dog, these experiments suggest that the disposition of ciramadol in man would not be affected by coadministration of lorazepam, whereas the potential for a diazepam/ciramadol drug interaction in humans exists.

Amines↗
PubMedDate not supplied

The metabolic disposition of norgestrel in female rhesus monkeys.

Following single intragastric doses of d- and dl-[24C]norgestrel (Ng), rhesus monkeys excreted 29.5 +/- 2.0 (SE) and 52.6 +/- 5.4% of the administered radioactivity in urine. Fecal excretion accounted for 57.1 +/- 4.0 and 37.2 +/- 4.4%, respectively. Urinary radioactivity was separated into neutral, acidic, and conjugated fractions. The neutral and conjugated fractions contained Ng; 2 alpha, 16 alpha- and 16 beta-hydroxy-Ng; 3 alpha,5 beta-tetrahydro-Ng and 16 beta-hydroxy-3 alpha,5 beta-tetrahydro-Ng and their glucuronides. However, the bulk of the radioactivity in these fractions was associated with more polar metabolites. The acidic fraction contained unstable metabolies which lose 14CO2 at pH values below 5. The most abundant of these metabolites was isolated as its stable methyl ester. The structure of a 13-ethyl-D-homogon-4-ene-3,17 alpha-dione-17 carboxylic acid is proposed for the metabolite which decomposes to 13-ethyl-D-homogon-4-ene-3,17 alpha-dione [D-homo-G]. The probable mechanism of the metabolite's formation is postulated. Quantitative differences in urinary metabolite patterns were observed following the administration of d- and dl-Ng. Ng is the major identified drug-related entity in plasma. The d-Ng concentrations in plasma measured by radioimmunoassay were in good agreement with those determined by fractionation and radiometry. The latter method indicated the presence of D-homo-G and a glucuronide of 3 alpha,5 beta-tetrahydro-Ng following the administration of d- and dl-Ng.

Animals↗