1. Estimating Efflux Transporter-Mediated Disposition of Molecules beyond the Rule of Five (bRo5) Using Transporter Gene Knockout Rats.
- Author
-
Miyake T
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters genetics, Administration, Oral, Animals, Benzimidazoles administration & dosage, Benzimidazoles blood, Biological Availability, Cyclopropanes administration & dosage, Cyclopropanes blood, Cyclosporine administration & dosage, Cyclosporine blood, Fluorenes administration & dosage, Fluorenes blood, Gene Knockout Techniques, Isoindoles administration & dosage, Isoindoles blood, Isoquinolines administration & dosage, Isoquinolines blood, Lactams, Macrocyclic administration & dosage, Lactams, Macrocyclic blood, Male, Metabolic Clearance Rate genetics, Oral Mucosal Absorption genetics, Proline administration & dosage, Proline blood, Proline pharmacokinetics, Rats, Rats, Sprague-Dawley, Simeprevir administration & dosage, Simeprevir blood, Sulfonamides administration & dosage, Sulfonamides blood, ATP-Binding Cassette Transporters deficiency, Benzimidazoles pharmacokinetics, Cyclopropanes pharmacokinetics, Cyclosporine pharmacokinetics, Fluorenes pharmacokinetics, Isoindoles pharmacokinetics, Isoquinolines pharmacokinetics, Lactams, Macrocyclic pharmacokinetics, Proline analogs & derivatives, Simeprevir pharmacokinetics, Sulfonamides pharmacokinetics
- Abstract
Transporter gene knockout models are a practical and widely used tool for pharmacokinetic studies in drug discovery. P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are major efflux transporters that control absorption and bioavailability, and are important when determining oral drug disposition. To the best of our knowledge, beyond the rule of five (bRo5) molecules launched on the market to date tend to be substrates for efflux transporters. The purpose of this study is to evaluate in vivo the impact of efflux transporters on the oral absorption process and systemic clearance using rats which lack P-gp and/or Bcrp expression. We administered five bRo5 substrates (asunaprevir, cyclosporine, danoprevir, ledipasvir, and simeprevir) intravenously or orally to wild-type and Mdr1a, Bcrp, and Mdr1a/Bcrp knockout rats, calculated the clearance, oral bioavailability, and absorption rate profile of each substrate, and compared the results. Systemic clearance of the substrates in knockout rats changed within approximately ±40% compared to wild-types, suggesting the efflux transporters do not have a significant influence on clearance in rats. On the other hand, the oral absorption of substrates in the knockout rats, especially those lacking Mdr1a, increased greatly-between 2- and 5-fold more than in wild-types. This suggests that rat efflux transporters, especially P-gp, greatly reduce the oral exposure of these substrates. Moreover, results on the absorption rate-time profile suggest that efflux transporters are constantly active during the absorption period in rats. Transporter knockout rats are a useful in vivo tool for estimating the transporter-mediated disposition of bRo5 molecules in drug discovery.
- Published
- 2020
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