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Acitretin elimination in Sprague-Dawley rats pretreated with phenobarbital or beta-naphthoflavone.
Drug Metab Dispos. 1995 Apr; 23(4):465-72.DM

Abstract

Male Sprague-Dawley rats were pretreated with either phenobarbital (PB) or beta-naphthoflavone (BNF), after which acitretin (0.84-0.86 mg/kg) was administered intravenously and plasma was sampled with time. Animals were killed 24 hr after dosing, and livers were removed. Hepatic microsomal protein was isolated, frozen, and later used for quantitation of hepatic microsomal protein concentration, total cytochrome P450 concentration, and microsomal activities of methoxy-, ethoxy-, pentoxy-, and benzyloxyresorufin O-dealkylation (MROD, EROD, PROD, and BROD, respectively). Plasma concentrations of acitretin and its primary metabolite isoacitretin were quantified by reversed-phase HPLC. PB pretreatment increased the systemic clearance (CLs) of acitretin 33%, but did not statistically significantly affect the volume of distribution (Vss) or mean residence time (MRT). PB pretreatment increased hepatic microsomal protein and total P450 concentrations, and increased the activity of MROD 7-fold, EROD 8-fold, PROD 121-fold, and BROD 106-fold. BNF pretreatment increased acitretin CLs 152% and reduced MRT by two-thirds; Vss was unchanged. Hepatic microsomal protein and total P450 concentrations were increased after BNF pretreatment, as were the activities of MROD 20-fold, EROD 32-fold, PROD 1-fold, and BROD 6-fold. These results indicate that PB moderately induces acitretin CLs in Sprague-Dawley rats, but the magnitude of induction suggests that the predominant PB-inducible enzymes do not play a major role in acitretin elimination. BNF pretreatment substantially increased acitretin CLs in male Sprague-Dawley rats, which strongly implicates involvement of P4501A1 and/or 1A2, and suggests the potential for clinically relevant interactions between acitretin disposition and drugs and activities that induce these pathways.

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Authors+Show Affiliations

Small DS
Division of Pharmacology and Experimental Therapeutics, University of Kentucky College of Pharmacy, USA.
McNamara PJ
No affiliation info available

MeSH

AcitretinAnimalsBenzoflavonesBiotransformationChromatography, High Pressure LiquidCytochrome P-450 Enzyme SystemEnzyme InductionLiverMaleMicrosomes, LiverOrgan SizePhenobarbitalRatsRats, Sprague-Dawleybeta-Naphthoflavone

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

7600913

Citation

Small, D S., and P J. McNamara. "Acitretin Elimination in Sprague-Dawley Rats Pretreated With Phenobarbital or Beta-naphthoflavone." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 23, no. 4, 1995, pp. 465-72.
Small DS, McNamara PJ. Acitretin elimination in Sprague-Dawley rats pretreated with phenobarbital or beta-naphthoflavone. Drug Metab Dispos. 1995;23(4):465-72.
Small, D. S., & McNamara, P. J. (1995). Acitretin elimination in Sprague-Dawley rats pretreated with phenobarbital or beta-naphthoflavone. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 23(4), 465-72.
Small DS, McNamara PJ. Acitretin Elimination in Sprague-Dawley Rats Pretreated With Phenobarbital or Beta-naphthoflavone. Drug Metab Dispos. 1995;23(4):465-72. PubMed PMID: 7600913.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acitretin elimination in Sprague-Dawley rats pretreated with phenobarbital or beta-naphthoflavone. AU - Small,D S, AU - McNamara,P J, PY - 1995/4/1/pubmed PY - 1995/4/1/medline PY - 1995/4/1/entrez SP - 465 EP - 72 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 23 IS - 4 N2 - Male Sprague-Dawley rats were pretreated with either phenobarbital (PB) or beta-naphthoflavone (BNF), after which acitretin (0.84-0.86 mg/kg) was administered intravenously and plasma was sampled with time. Animals were killed 24 hr after dosing, and livers were removed. Hepatic microsomal protein was isolated, frozen, and later used for quantitation of hepatic microsomal protein concentration, total cytochrome P450 concentration, and microsomal activities of methoxy-, ethoxy-, pentoxy-, and benzyloxyresorufin O-dealkylation (MROD, EROD, PROD, and BROD, respectively). Plasma concentrations of acitretin and its primary metabolite isoacitretin were quantified by reversed-phase HPLC. PB pretreatment increased the systemic clearance (CLs) of acitretin 33%, but did not statistically significantly affect the volume of distribution (Vss) or mean residence time (MRT). PB pretreatment increased hepatic microsomal protein and total P450 concentrations, and increased the activity of MROD 7-fold, EROD 8-fold, PROD 121-fold, and BROD 106-fold. BNF pretreatment increased acitretin CLs 152% and reduced MRT by two-thirds; Vss was unchanged. Hepatic microsomal protein and total P450 concentrations were increased after BNF pretreatment, as were the activities of MROD 20-fold, EROD 32-fold, PROD 1-fold, and BROD 6-fold. These results indicate that PB moderately induces acitretin CLs in Sprague-Dawley rats, but the magnitude of induction suggests that the predominant PB-inducible enzymes do not play a major role in acitretin elimination. BNF pretreatment substantially increased acitretin CLs in male Sprague-Dawley rats, which strongly implicates involvement of P4501A1 and/or 1A2, and suggests the potential for clinically relevant interactions between acitretin disposition and drugs and activities that induce these pathways. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/7600913/Acitretin_elimination_in_Sprague_Dawley_rats_pretreated_with_phenobarbital_or_beta_naphthoflavone_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7600913 DB - PRIME DP - Unbound Medicine ER -