title: Effect of repeated dosing on rifampin exposure in BALB/c mice.
abstract: The discovery of novel therapeutics for the treatment of tuberculosis involves routine testing in a mouse model over four weeks of daily dosing with test compounds. In this model, daily oral administration of rifampin (10 mg/kg) showed significantly lower plasma exposure on day 5 compared to day 1. The absence of PXR-mediated induction of mouse Cyp3a isoforms was confirmed in the present study by incubating liver microsomes prepared from control and rifampin treated mice with probe substrates of CYP3A. To test whether the reduction in exposure was due to Pgp-mediated efflux, verapamil, a known Pgp inhibitor, was dosed to the rifampin pre-treated mice which led to an increase in exposure to that obtained after a single dose of rifampin, suggesting the role of Pgp induction in reducing exposure to rifampin. To further confirm Pgp induction in rifampin treated mice, digoxin, a known substrate of Pgp, was administered to the rifampin pre-treated mice, and a significant drop in the digoxin exposure was observed compared to the control group. Collectively, our results show that repeated administration of rifampin in mice leads to a reduction in oral exposure due to induction of Pgp-mediated efflux of rifampin, and not via induction of CYP3A isoforms.
authors: Drug Metabolism and Pharmacokinetics, Infection iMED, AstraZeneca India Pvt. Ltd., Bangalore, India. Electronic address: vinayak.hosagrahara@astrazeneca.com.
authors: Vinayak
authors: V
authors: Hosagrahara
authors: Drug Metabolism and Pharmacokinetics, Infection iMED, AstraZeneca India Pvt. Ltd., Bangalore, India.
authors: Jitendar
authors: J
authors: Reddy
authors: Drug Metabolism and Pharmacokinetics, Infection iMED, AstraZeneca India Pvt. Ltd., Bangalore, India.
authors: Samit
authors: S
authors: Ganguly
authors: Drug Metabolism and Pharmacokinetics, Infection iMED, AstraZeneca India Pvt. Ltd., Bangalore, India.
authors: Vijender
authors: V
authors: Panduga
authors: Drug Metabolism and Pharmacokinetics, Infection iMED, AstraZeneca India Pvt. Ltd., Bangalore, India.
authors: Vijaykamal
authors: V
authors: Ahuja
authors: Drug Metabolism and Pharmacokinetics, Infection iMED, AstraZeneca India Pvt. Ltd., Bangalore, India.
authors: Manish
authors: M
authors: Parab
authors: Drug Metabolism and Pharmacokinetics, Infection iMED, AstraZeneca India Pvt. Ltd., Bangalore, India.
authors: Jayashree
authors: J
authors: Giridhar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012293:Rifampin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin