The metabolism of ethyl 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetate (TA-1801), a potent hypolipidemic agent, was studied in humans after oral administration and compared with that found in rats, rabbits, and dogs previously. Hydrolysis of the ethyl ester to produce metabolite M1 (TA-1801 active form; TA-1801A) is the first metabolic step and the subsequent biotransformation includes the glucuronidation to form the metabolite M4 and the oxidation to form the metabolites M2 and M3. The metabolism of TA-1801 in humans was qualitatively similar to that in the experimental animals studied, although species differences were seen in the amount of metabolites. M4, the glucuronide of TA-1801A was the most abundant metabolite in human urine (24.3% of the dose). In vitro studies using human liver and jejunum microsomes indicated that the TA-1801A glucuronosyltransferase activity in human jejunum microsomes was 2-fold higher than that in liver microsomes. With regard to the interspecies differences in the TA-1801A glucuronosyltransferase activities, the intrinsic clearance for the TA-1801A glucuronidation in liver microsomes was in the following order: rabbit>monkey>human=rat=dog. In jejunum microsomes, the intrinsic clearance for the TA-1801A glucuronidation was in the following order: human>monkey>rabbit>rat=dog. These results suggest that the species differences in the intestinal TA-1801A glucuronidation contribute to the species differences in the excretion rate of TA-1801A glucuronide into the urine.

Drug metabolism and disposition: the biological fate of chemicals

Metabolism of ethyl 2-(4-chlorophenyl)-5-(2-furyl)-oxazole-4-acetate, a new hypolipidemic agent, in the rat, rabbit, and dog. Glucuronidation of carboxyl group and cleavage of furan ring.

Article

Author: Harigaya, S ; Sugihara, J ; Kobayashi, T ; Ando, H

Metabolism of ethyl 2-(4-chlorophenyl)-5-(2-furyl)-oxazole-4-acetate (TA-1801), a new hypolipidemic agent, was studied in the rat, rabbit, and dog. Animals were given a single oral dose of 50 mg/kg TA-1801 labeled with 14C. The first metabolic reaction for TA-1801 was hydrolysis of the ester linkage. The resulting metabolite M1 was found to undergo further biotransformations, i.e. glucuronidation at the carboxyl group and ring cleavage of the furan group. These metabolic pathways were observed in all the species examined, although species differences were seen in the amount of metabolites.

Drug metabolism and disposition: the biological fate of chemicals

Mechanism of metabolic cleavage of a furan ring.

Article

Author: Kobayashi, T ; Harigaya, S ; Sugihara, J

We studied the mechanism of metabolic cleavage of a furan ring, using a new hypolipidemic agent, ethyl 2-(4-chlorophenyl)-5-(2-furyl)oxazole-4-acetate (TA-1801), as a model compound. A TA-1801 analogue labeled with deuterium at the 5-position of its furan ring was administered orally to rats. The analysis of urinary metabolites by GC/MS revealed that the deuterium of the furan was retained in the ring-opened metabolite (M3). Metabolic cleavage of furan has been generally considered to proceed by hydroxylation of the 5-position followed by tautomerism and hydrolysis of the resulting 5-hydroxyfuran derivative. However, if the cleavage proceeded by this pathway, the deuterium of the 5-position would be eliminated during hydroxylation. Therefore, we propose that the ring was cleaved directly to form an unsaturated aldehyde, considering the mechanism of oxidation by cytochrome P-450. Although this "intermediate" was not detected in the biological specimens, a synthetic unsaturated aldehyde was transformed to the actual urinary metabolites M2 and M3 (major ring-opened metabolites) in the isolated rat liver.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypercholesterolemia	Phase 2	JP	Mitsubishi Tanabe Pharma Corp.	-

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