Formation of thymine-lysine adducts in irradiated DNA-lysine systems.
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Binding Sites↗
Biomedical subjects
E T Lin
Publications and source records attributed to E T Lin.
Pharmacokinetics of nitroglycerin and metabolites in humans following oral dosing.
Single dose oral nitroglycerin (GTN) was administered to six healthy subjects as 6.5, 9.0, and 13.0 mg aqueous solutions in sequential study phases to characterize the oral pharmacokinetics of GTN and the dinitrate metabolites. Blood samples were collected periodically up to 10 h. Plasma concentrations of GTN were measurable in some subjects up to 1/2 and 1 h, respectively, after the 9.0 and 13.0 mg dose. The mean GTN Cmax values of the three solution doses were 0.28, 0.78, and 0.42 ng ml-1 in ascending dosage. The erratic nature of GTN plasma profiles prevented meaningful pharmacokinetic analysis, although tmax was consistently 5 min. In all three treatments, both GTN metabolites (1,2- and 1,3-glyceryldinitrates, GDNs) peaked at about 20 min, followed by a distributive phase and a log-linear decline in concentrations. Terminal half-lives for both GDNs were approximately 50 min in all three doses. The plasma concentrations of the metabolites were higher than nitroglycerin with 1,2-GDN exhibiting the highest overall profile.
Administration, Oral↗
Influence of probenecid on the urinary excretion rates of the diastereomeric benoxaprofen glucuronides.
A major biotransformation pathway for many NSAIDs from the group of optically active 2-arylpropionic acids is the conjugation with D-glucuronic acid, forming diastereomers. These conjugates of the S-(+)-and the R-(-)-enantiomers can be separated directly, e.g., by ion-pair chromatography on a C18-column using a mixture of tetrabutylammonium buffer pH 2.5 and acetonitrile as mobile phase. In man about 40% of the dose was recovered in urine as glucuronides (ratio S:R = 2.2) within 96 hours of p.o. administration of racemic drug. When probenecid, which is known to influence the elimination of several acidic drugs, was administered in addition, the amount excreted as glucuronides during 4 days was clearly reduced. Furthermore, the enantiomeric ratio was changed significantly, possibly because of an increase of stereoinversion due to the reduced drug clearance.
Anti-Inflammatory Agents, Non-Steroidal↗
Stereoselective disposition of ketoprofen in rats.
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Animals↗
Stereoselective disposition of carprofen, flunoxaprofen, and naproxen in rats.
The stereoselective dispositions of carprofen, flunoxaprofen, and naproxen were studied in rats after i.v. administration of racemate (11 mumol/kg) or enantiomer (5.5 mumol/kg). The total clearances of the (R)-enantiomers of carprofen and flunoxaprofen were significantly greater than those of the (S)-enantiomers. The clearance of (S)-naproxen was similar to the value for (R)-naproxen. There were no marked differences in steady-state volume of distribution between (R)- and (S)-enantiomers for carprofen, flunoxaprofen, or naproxen. The (R)- to (S)-enantiomer inversion ratio for flunoxaprofen in rats was 0.54. The ratios for naproxen and carprofen were 0.02 and 0.003, respectively. Biliary excretion of (R)-carprofen and of its glucuronide were higher than those of the (S)-enantiomer and its glucuronide. In contrast, biliary excretion of the (S)-enantiomers of flunoxaprofen, naproxen, and of their glucuronides were greater than those of their antipodes. Insignificant amounts of the parent enantiomers and of the glucuronides of these three drugs were excreted in urine. These results indicate that there is a wide variation in the extent of inversion at a chiral center for these three 2-arylpropionates and in the stereoselective disposition of their acyl glucuronides.
Animals↗
Direct determination of diastereomeric carprofen glucuronides in human plasma and urine and preliminary measurements of stereoselective metabolic and renal elimination after oral administration of carprofen in man.
A direct stereospecific HPLC assay for carprofen glucuronides in biologic fluids was developed that makes use of a reverse phase (C 18) gradient system, in which the mobile phase consisted of a mixture of acetonitrile and tetrabutylammonium hydroxide buffer (pH 2.5). Reference diastereomeric glucuronides of carprofen were purified from human urine after oral administration of the single enantiomers. When 0.1 ml of sample was used, the limit of detection for carprofen glucuronides was 50 ng/ml in plasma and 200 ng/ml in urine. Coefficients of variation did not exceed 12% for both intra and interday variability. This HPLC method is applicable to pharmacokinetic analysis for carprofen glucuronides in humans. After oral administration of the single enantiomers there was little indication of metabolic inversion. For the two enantiomers the apparent total and metabolic clearances were similar. The limited data available suggest that renal clearance of the (S)-glucuronide was greater than that of the (R)-glucuronide.
Administration, Oral↗
Absorption and disposition of furosemide in healthy volunteers, measured with a metabolite-specific assay.
The objectives of this study were to qualitatively and quantitatively compare the metabolism, pharmacokinetics, and bioavailability of furosemide in healthy volunteers after intravenous and oral administration. We also determined the plasma protein binding of furosemide in vivo after iv administration. Nine males received furosemide (Hoechst, 40 mg iv and 80 mg po) in a random crossover fashion. Serial plasma samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced throughout the study. Furosemide as well as its potential metabolites were measured by a rapid, sensitive, and specific spectrofluorimetric HPLC assay. Total plasma clearance averaged 164 +/- 26 (SD) ml/min, of which 66.2 +/- 6.8% represented renal clearance of unchanged drug. Volume of distribution (steady-state) was 109 +/- 19 ml/kg. These clearance and volume measurements are in good agreement with data previously published by our group. The mean absolute bioavailability of furosemide was 42.8 and 44.0%, as calculated from plasma and urine data, respectively. Protein binding of furosemide in vivo was determined by a spectrofluorimetric HPLC assay and ranged from 98.5 to 99.1%. Approximately 5.5 mg of furosemide was excreted as a glucuronide conjugate after iv dosing and about 5.1 mg after po administration. We found no evidence of the proposed metabolite of furosemide, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA) in any of our plasma or urine samples. In addition, we conclusively demonstrated CSA to be an analytical artifact.
Absorption↗