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Estimating Efflux Transporter-Mediated Disposition of Molecules beyond the Rule of Five (bRo5) Using Transporter Gene Knockout Rats.
- Source :
-
Biological & pharmaceutical bulletin [Biol Pharm Bull] 2020 Mar 01; Vol. 43 (3), pp. 384-392. Date of Electronic Publication: 2019 Nov 02. - Publication Year :
- 2020
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1347-5215
- Volume :
- 43
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biological & pharmaceutical bulletin
- Publication Type :
- Academic Journal
- Accession number :
- 31685755
- Full Text :
- https://doi.org/10.1248/bpb.b19-00641