Evaluating the disposition of a mixed aldehyde oxidase/cytochrome P450 substrate in rats with attenuated P450 activity

Rachel D. Crouch, Ryan D. Morrison, Frank W. Byers, Craig W. Lindsley, Kyle Allen Emmitte, J. Scott Daniels

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Abstract

Marketed drugs cleared by aldehyde oxidase (AO) are few, with no known clinically relevant pharmacokinetic drug interactions associated with AO inhibition, whereas cytochrome P450 (P450) inhibition or induction mediates a number of clinical drug interactions. Little attention has been given to the consequences of coadministering a P450 inhibitor with a compound metabolized by both AO and P450. Upon discovering that VU0409106 (1) was metabolized by AO (to M1) and P450 enzymes (to M4-M6), we sought to evaluate the in vivo disposition of 1 and its metabolites in rats with attenuated P450 activity. Male rats were orally pretreated with the pan-P450 inactivator, 1-aminobenzotriazole (ABT), before an i.p. dose of 1. Interestingly, the plasma area under the curve (AUC) of M1 was increased 15-fold in ABT-treated rats, indicating a metabolic shunt toward AO resulted from the drug interaction condition. The AUC of 1 also increased 7.8-fold. Accordingly, plasma clearance of 1 decreased from 53.5 to 15.3 ml/min per kilogramin ABT-pretreated rats receiving an i.v. dose of 1. Consistent with these data, M1 formation in hepatic S9 increased with NADPH-exclusion to eliminate P450 activity (50% over reactions containing NADPH). These studies reflect possible consequences of a drug interaction between P450 inhibitors and compounds cleared by both AO and P450 enzymes. Notably, increased exposure to an AO metabolite may hold clinical relevance for active metabolites or those mediating toxicity at elevated concentrations. The recent rise in clinical drug candidates metabolized by AO underscores the importance of these findings and the need for clinical studies to fully understand these risks.

Original languageEnglish
Pages (from-to)1296-1303
Number of pages8
JournalDrug Metabolism and Disposition
Volume44
Issue number8
DOIs
StatePublished - 1 Aug 2016

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Aldehyde Oxidase
Cytochrome P-450 Enzyme System
Drug Interactions
NADP
Area Under Curve
Pharmaceutical Preparations
Pharmacokinetics

Cite this

Crouch, Rachel D. ; Morrison, Ryan D. ; Byers, Frank W. ; Lindsley, Craig W. ; Emmitte, Kyle Allen ; Daniels, J. Scott. / Evaluating the disposition of a mixed aldehyde oxidase/cytochrome P450 substrate in rats with attenuated P450 activity. In: Drug Metabolism and Disposition. 2016 ; Vol. 44, No. 8. pp. 1296-1303.
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abstract = "Marketed drugs cleared by aldehyde oxidase (AO) are few, with no known clinically relevant pharmacokinetic drug interactions associated with AO inhibition, whereas cytochrome P450 (P450) inhibition or induction mediates a number of clinical drug interactions. Little attention has been given to the consequences of coadministering a P450 inhibitor with a compound metabolized by both AO and P450. Upon discovering that VU0409106 (1) was metabolized by AO (to M1) and P450 enzymes (to M4-M6), we sought to evaluate the in vivo disposition of 1 and its metabolites in rats with attenuated P450 activity. Male rats were orally pretreated with the pan-P450 inactivator, 1-aminobenzotriazole (ABT), before an i.p. dose of 1. Interestingly, the plasma area under the curve (AUC) of M1 was increased 15-fold in ABT-treated rats, indicating a metabolic shunt toward AO resulted from the drug interaction condition. The AUC of 1 also increased 7.8-fold. Accordingly, plasma clearance of 1 decreased from 53.5 to 15.3 ml/min per kilogramin ABT-pretreated rats receiving an i.v. dose of 1. Consistent with these data, M1 formation in hepatic S9 increased with NADPH-exclusion to eliminate P450 activity (50{\%} over reactions containing NADPH). These studies reflect possible consequences of a drug interaction between P450 inhibitors and compounds cleared by both AO and P450 enzymes. Notably, increased exposure to an AO metabolite may hold clinical relevance for active metabolites or those mediating toxicity at elevated concentrations. The recent rise in clinical drug candidates metabolized by AO underscores the importance of these findings and the need for clinical studies to fully understand these risks.",
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Evaluating the disposition of a mixed aldehyde oxidase/cytochrome P450 substrate in rats with attenuated P450 activity. / Crouch, Rachel D.; Morrison, Ryan D.; Byers, Frank W.; Lindsley, Craig W.; Emmitte, Kyle Allen; Daniels, J. Scott.

In: Drug Metabolism and Disposition, Vol. 44, No. 8, 01.08.2016, p. 1296-1303.

Research output: Contribution to journalArticleResearchpeer-review

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