2017

In Vitro Studies with Two Human Organic Anion Transporters: OAT2 & OAT7

Published:  25 September 2017

Mathialagan S, Costales C, Tylaska L, Kimoto E, Vildhede A, Johnson J, Johnson N, Sarashina T, Hashizume K, Isringhausen CD, Vermeer LMM, Wolff AR, Rodrigues AD

Penciclovir, ganciclovir, creatinine, para-aminohippuric acid (PAH), ketoprofen, estrone 3-O-sulfate (E3S), dehydroepiandrosterone 3-O-sulfate (DHEAS), and cyclic guanosine monophosphate (cGMP) were screened as substrates of human liver organic anion transporters OAT2 and OAT7. For OAT7, high uptake ratios (versus mock transfected HEK293 cells) of 29.6 and 15.3 were obtained with E3S and DHEAS. Less robust uptake ratios (≤ 3.6) were evident with the other substrates. OAT2 (transcript variant 1, OAT2-tv1) presented high uptake ratios of 30, 13, ∼35, ∼25, 8.5, and 9 with cGMP, PAH, penciclovir, ganciclovir, creatinine, and E3S, respectively. No uptake was observed with DHEAS. Although not a substrate of either transporter, ketoprofen did inhibit transfected OAT2-tv1 (IC50 of 17, 22, 23, 24, 35, and 586 μM; creatinine, ganciclovir, penciclovir, cGMP, E3S, and prostaglandin F2α, respectively) and penciclovir uptake (IC50 = 27 µM; >90% inhibition) by plated human hepatocytes (PHH). It is concluded that penciclovir and ketoprofen may serve as useful tools for the assessment of OAT2 activity in PHH. However, measurement of OAT7 activity therein will prove more challenging, as high uptake rates are evident with E3S and DHEAS only and both sulfoconjugates are known to be substrates of organic anion transporting polypeptides.

DDI Guidance Recommendations on Down-Regulation, CYP2C Induction and CYP2B6 Control

Published:  23 June 2017

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on Down-regulation, CYP2C Induction and CYP2B6 Positive Control

The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency and the Food and Drug Administration have issued guidances for the conduct of drug-drug interaction (DDI) studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (WG). A team of 20 scientists, from 16 of the 39 pharmaceutical companies, which are members of the IQ Consortium, and three Contract Research Organizations, reviewed the recommendations, focusing initially on the current EMA guidance. Questions were collated from IQ member companies as to which aspects of the guidance required further evaluation. The EMA was then approached to provide insights into their recommendations on the following points; a) evaluation of down-regulation, b) in vitro assessment of CYP2C induction, c) the recommendation to use CITCO as the positive control for CYP2B6 induction, d) data interpretation (two-fold increase in mRNA as evidence of induction), and e) duration of incubation of hepatocytes with test article. The Induction WG conducted an anonymous survey among IQ member companies to query current practices, specifically focusing on how the aforementioned key points are evaluated. Responses were received from 19 companies. All data/information was blinded prior to being shared with the Induction WG. The results of the survey are presented together with consensus recommendations on down-regulation, CYP2C induction and CYP2B6 positive control. Data interpretation and incubation duration will be reported in subsequent manuscripts.