scholarly journals Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans

2011 ◽  
pp. 77-92
Author(s):  
Julie Scholler ◽  
Dominique Leveque
Keyword(s):  
Drug Interactions ◽  
Nuclear Receptors ◽  
Kinase Inhibitors ◽  
Drug Disposition ◽  
Clinical Impact ◽  
Published Data ◽  
Drug Metabolizing Enzymes ◽  
Orphan Nuclear Receptors ◽  
Metabolizing Enzymes ◽  
Molecular Determinants

This review presents the published data regarding the molecular determinants (drug metabolizing enzymes, drug transporters and orphan nuclear receptors) of approved anticancer kinase inhibitors pharmacokinetics in humans. The clinical impact of these determinants (drug disposition and drug–drug interactions) is also discussed.

scholarly journals Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans

2011 ◽  
Vol 5 (2) ◽  
pp. 77 ◽  
Author(s):  
Julie Scholler ◽  
Dominique Leveque
Keyword(s):  
Drug Interactions ◽  
Nuclear Receptors ◽  
Kinase Inhibitors ◽  
Drug Disposition ◽  
Clinical Impact ◽  
Published Data ◽  
Drug Metabolizing Enzymes ◽  
Orphan Nuclear Receptors ◽  
Metabolizing Enzymes ◽  
Molecular Determinants

This review presents the published data regarding the molecular determinants (drug metabolizing enzymes, drug transporters and orphan nuclear receptors) of approved anticancer kinase inhibitors pharmacokinetics in humans. The clinical impact of these determinants (drug disposition and drug–drug interactions) is also discussed.

Regulation of brain drug metabolizing enzymes and transporters by nuclear receptors

2018 ◽  
Vol 50 (4) ◽  
pp. 407-414 ◽  
Author(s):  
Dan Xu ◽  
Songqiang Huang ◽  
Hui Wang ◽  
Wen Xie
Keyword(s):  
Nuclear Receptors ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes

scholarly journals In Vitro Evaluation of the Drug Interaction Potential of Doravirine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Kelly Bleasby ◽  
Kerry L. Fillgrove ◽  
Robert Houle ◽  
Bing Lu ◽  
Jairam Palamanda ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Reversible Inhibitor ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter ◽  
Major Drug

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

Sign in / Sign up

Export Citation Format

Share Document