Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 2: Prediction of Decreased Substrate Exposure After Rifabutin or Carbamazepine.
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Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, Worth A, Kearney BP, Mathias A
Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 2: Prediction of Decreased Substrate Exposure After Rifabutin or Carbamazepine.
Clin Pharmacol Ther. 2018 Mar 23. doi: 10.1002/cpt.1072.
- PubMed ID
- 29569712 [ View in PubMed]
- Abstract
Rifampin demonstrated dose-dependent relative induction between cytochrome P (CYP)3A and P-glycoprotein (P-gp), organic anion transporting polypeptides (OATPs), or CYP2C9; P-gp, OATP, and CYP2C9 induction was one drug-drug interaction (DDI) category lower than that observed for CYP3A across a wide range of pregnane X receptor (PXR) agonism. The objective of this study was to determine if these relationships could be utilized to predict transporter induction by other CYP3A inducers (rifabutin and carbamazepine) and of another P-gp substrate, sofosbuvir. Healthy subjects received sofosbuvir and a six-probe drug cassette before and after 300 mg q.d. rifabutin or 300 mg b.i.d. carbamazepine. Induction of P-gp, CYP2C9, and decreased sofosbuvir exposure were successfully predicted by observed CYP3A induction. Carbamazepine induction of OATP was underpredicted, likely due to reported additional non-PXR agonism. The results demonstrate that the effect of a PXR agonist on CYP3A can be leveraged to inform on induction liability for other primarily PXR-regulated P450s/transporters, allowing for prioritization of targeted DDI assessments during new drug development.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Rifabutin Cytochrome P450 2C9 Protein Humans NoInducerDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Rifabutin P-glycoprotein 1 Protein Humans UnknownInducerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareRaltegravirRifabutin The serum concentration of Raltegravir can be decreased when it is combined with Rifabutin. SofosbuvirRifabutin The serum concentration of Sofosbuvir can be decreased when it is combined with Rifabutin.