Biomedical subjects

F S Abbott

Publications and source records attributed to F S Abbott.

76 records · Page 5Linked to original sources

PubMedDate not supplied

Pharmacokinetics and enterohepatic circulation of 2-n-propyl-4-pentenoic acid in the rat.

The pharmacokinetics of 4-ene-valproic acid (4-ene-VPA), a putative hepatotoxic metabolite of the anticonvulsant valproic acid (VPA), were studied in normal and bile-exteriorized rats. A single iv bolus dose of 20 or 100 mg/kg of 4-ene-VPA was administered to each rat. Plasma decline of 4-ene-VPA was apparently monoexponential at the low dose and nonlinear at the high dose. In normal rats, 4-ene-VPA was recycled in the plasma due to enterohepatic circulation (EHC). A time lag pharmacokinetic model was used to describe the plasma profile, including the appearance of a secondary plasma peak, in normal animals receiving the low dose of 4-ene-VPA. Total apparent plasma clearance was 8.67 ml/min.kg at the low dose and 5.89 ml/min.kg at the high dose. EHC was abolished in bile-exteriorized animals. In these rats, the apparent plasma elimination half-life increased from 12.7 to 18.8 min and plasma clearance decreased from 11.4 to 7.41 ml/min.kg with a 5-fold increase in the dose. 4-ene-VPA was largely eliminated in urine and bile as conjugates. In normal rats, 22% and 28% of the low and high dose, respectively, were eliminated in urine. Approximately 29% of the low dose and 21% of the high dose were recovered in bile of the rat. Like the parent drug VPA, 4-ene VPA induced dose-dependent choleresis in the rat. The pharmacokinetics of 4-ene-VPA in the rat were similar to those reported for VPA.

Animals↗

PubMedDate not supplied

Identification of carbamoylated thiol conjugates as metabolites of the antineoplastic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, in rats and humans.

The metabolic fate of 1-(2-chloroethyl)-3-cyclohexyl)-nitrosourea (CCNU) in rats and humans was investigated with a view to characterizing the nature of the carbamoylating species released upon in vivo transformation of the drug. CCNU undergoes oxidation in vivo to afford 4-hydroxy and 3-hydroxy CCNU which, along with the parent drug, decomposes to the corresponding isocyanates. Although the highly reactive nature of the isocyanate species precludes their identification in vivo, their existence as electrophilic intermediates was detected in the likeness of trapped glutathione (GSH) and N-acetylcysteine (NAC) conjugates. Conjugated thiol metabolites were purified by HPLC from the bile and urine of CCNU-dosed rats, and the urine of a patient on CCNU therapy. The metabolites were identified by atmospheric pressure chemical ionization LC/MS and LC/MS/MS. In addition, LC/MS and LC/MS/MS spectra of synthesized authentic standards corroborated the identity of the metabolites. In rats, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, and cyclohexyl isocyanate were identified as their GSH conjugates in bile and NAC conjugates in urine. In the case of the patient, the NAC conjugates of 4-hydroxycyclohexyl and 3-hydroxycyclohexyl isocyanate were identified as urinary metabolites. The identification of GSH and NAC conjugates reported herein marks a significant advance in the assessment of the in vivo carbamoylating activity of CCNU and its phase I metabolites.

Acetylcysteine↗

PubMedDate not supplied

Disposition, metabolism, and pharmacodynamics of labetalol in adult sheep.

Labetalol causes significant maternal and fetal metabolic effects in pregnant sheep (Yeleswaram et al., J. Pharmacol. Exp. Ther. 262, 683-691 (1992)). This study was undertaken to investigate the contribution of skeletal muscles in the development of metabolic acidosis induced by labetalol and to explore the involvement of active metabolite(s) using conscious, chronically instrumented adult nonpregnant ewes. Following a 100 mg iv bolus, the disposition of labetalol was similar to that observed in pregnant sheep. The effects of labetalol included hypotension, reflex tachycardia, a significant increase in femoral blood flow, hyperglycemia, lactic acidosis, and increased hind limb oxygen consumption. The arteriovenous flux of labetalol, glucose, lactate, and oxygen across the hindlimb was calculated using the Fick principle. The net output of lactate from the hindquarter over 12 hr following drug administration was calculated to be 6.25 +/- 1.35 g (0.07 +/- 0.015 mol). Glucuronidation, sulfation, and oxidative metabolism of labetalol were studied using urine and bile samples. The cumulative urinary excretion of labetalol as unchanged drug, glucuronide and sulfate was found to be 1.61 +/- 0.3, 11.46 +/- 2.83, and 1.47 +/- 0.74% of the dose, respectively. Using GC-mass selective detection, the presence of 3-amino-1-phenylbutane (3-APB), a close congener of amphetamine, in urine and bile samples was established. The cumulative excretion of 3-APB in urine represents 0.044 +/- 0.016% of the dose. Pharmacokinetic analysis shows the apparent elimination half-life of the metabolite to be 13.5 +/- 3.8 min. Conjugates of 3-APB were also found in the bile and urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Metabolic profiling of clobazam, a 1,5-benzodiazepine, in rats.

The metabolism of the 1,5-benzodiazepine clobazam (CLBZ) was investigated in the rat and in vitro by GC/MS using stable isotope techniques. Coadministration of CLBZ and pentadeuteriophenyl CLBZ to rats facilitated the identification of 4'-hydroxy CLBZ 7,4'-hydroxy N-desmethylclobazam (4'-hydroxy DMC) 5, 3',4'-dihydroxy CLBZ 13, 4'-hydroxy-3'-methoxy CLBZ 14, 3'-hydroxy-4'-methoxy CLBZ 15, and 4'-hydroxy-3'-methoxy DMC 16 in bile as both glucuronide and sulfate conjugates. Metabolites 7, 13, and 14 were present in urine as sulfate conjugates. 4'-Hydroxy CLBZ and 4'-hydroxy-3'-methoxy CLBZ were the major conjugated metabolites in bile and urine, respectively. An unusual in vivo disposition of CLBZ to the O-methyl catechols was discovered. In bile, the para O-methyl catechol 15 constituted 2% of the O-methyl catechols as a glucuronide conjugate, in contrast to constituting 30% (of the O-methyl catechols) as a sulfate. This marks an unprecedented observation of a different catechol O-methyl isomer ratio within the same biological fluid for different conjugate pools. The isotope effect associated with the microsomal N-demethylation of trideuteriomethyl CLBZ was determined. The values of kH/kD were calculated at 5.07 +/- 0.37 (N = 3) and 3.88 +/- 0.23 (N = 4) for control and induced microsomes, respectively.

Animals↗