The pharmacokinetics of etretinate and its metabolites in the dog

P. Thongnopnua, J. W. Massarella, C. L. Zimmerman

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The pharmacokinetics and disposition of etretinate (ET) and its metabolites, etretin (ETA) and isoetretin (c-ETA), were studied in the dog. Administration of ET, ETA, and c-ETA by several routes of administration allowed the use of a physiologically based model to assess the relative contributions of absorption and presystemic metabolism to the oral bioavailability of these compounds. The large Vd(ss) (214 ± 228 liters/kg) of ET and terminal half-life of greater than 300 hr indicated the wide distribution and prolonged storage of ET in the tissues. After a dose of ET, its two metabolites, ETA and c-ETA, were also detectable in the plasma. The oral bioavailability of ET in the dog was 52.5% with 95.4% of the dose available for absorption from the gut lumen. Of the ET that was absorbed from the gut lumen, 26.4% and 25.5% was removed by the gut wall and liver, respectively. ETA was found to be a formation rate-limited metabolite of ET. Although the oral bioavailability of ETA could not be determined because of its administration was not possible by the iv route, it appeared that only 16% of an orally administered dose entered the portal circulation from the gut. c-ETA was detected after administration of either ET or ETA. ETA and c-ETA were shown to be interconvertible metabolites, but the equilibrium of the conversion between c-ETA and ETA favored the formation of ETA. The oral bioavailability of c-ETA was 42.4%, but the liver showed little metabolic activity toward c-ETA. The loss in bioavailability of c-ETA was almost entirely due to lack of absorption from the gut lumen and to metabolism in the gut wall.

Original languageEnglish (US)
Pages (from-to)473-480
Number of pages8
JournalDrug Metabolism and Disposition
Volume17
Issue number5
StatePublished - Jan 1 1989

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Etretinate
Pharmacokinetics
Metabolites
Dogs
Biological Availability
Acitretin
Metabolism
Liver
Half-Life
Tissue
Plasmas

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Thongnopnua, P., Massarella, J. W., & Zimmerman, C. L. (1989). The pharmacokinetics of etretinate and its metabolites in the dog. Drug Metabolism and Disposition, 17(5), 473-480.

The pharmacokinetics of etretinate and its metabolites in the dog. / Thongnopnua, P.; Massarella, J. W.; Zimmerman, C. L.

In: Drug Metabolism and Disposition, Vol. 17, No. 5, 01.01.1989, p. 473-480.

Research output: Contribution to journalArticle

Thongnopnua, P, Massarella, JW & Zimmerman, CL 1989, 'The pharmacokinetics of etretinate and its metabolites in the dog', Drug Metabolism and Disposition, vol. 17, no. 5, pp. 473-480.
Thongnopnua P, Massarella JW, Zimmerman CL. The pharmacokinetics of etretinate and its metabolites in the dog. Drug Metabolism and Disposition. 1989 Jan 1;17(5):473-480.
Thongnopnua, P. ; Massarella, J. W. ; Zimmerman, C. L. / The pharmacokinetics of etretinate and its metabolites in the dog. In: Drug Metabolism and Disposition. 1989 ; Vol. 17, No. 5. pp. 473-480.
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abstract = "The pharmacokinetics and disposition of etretinate (ET) and its metabolites, etretin (ETA) and isoetretin (c-ETA), were studied in the dog. Administration of ET, ETA, and c-ETA by several routes of administration allowed the use of a physiologically based model to assess the relative contributions of absorption and presystemic metabolism to the oral bioavailability of these compounds. The large Vd(ss) (214 ± 228 liters/kg) of ET and terminal half-life of greater than 300 hr indicated the wide distribution and prolonged storage of ET in the tissues. After a dose of ET, its two metabolites, ETA and c-ETA, were also detectable in the plasma. The oral bioavailability of ET in the dog was 52.5{\%} with 95.4{\%} of the dose available for absorption from the gut lumen. Of the ET that was absorbed from the gut lumen, 26.4{\%} and 25.5{\%} was removed by the gut wall and liver, respectively. ETA was found to be a formation rate-limited metabolite of ET. Although the oral bioavailability of ETA could not be determined because of its administration was not possible by the iv route, it appeared that only 16{\%} of an orally administered dose entered the portal circulation from the gut. c-ETA was detected after administration of either ET or ETA. ETA and c-ETA were shown to be interconvertible metabolites, but the equilibrium of the conversion between c-ETA and ETA favored the formation of ETA. The oral bioavailability of c-ETA was 42.4{\%}, but the liver showed little metabolic activity toward c-ETA. The loss in bioavailability of c-ETA was almost entirely due to lack of absorption from the gut lumen and to metabolism in the gut wall.",
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