Abstract | OBJECTIVES: METHODS:
Enzyme kinetic parameters were determined using human liver microsomes for the biotransformation of EE to its glucuronide metabolites, and the potency and mechanism of inhibition by paritaprevir. Probenecid was used as a reference inhibitor for purposes of assay validation. KEY FINDINGS: The underlying pattern of EE kinetics was complex, with evidence of substrate inhibition. The in-vitro inhibition constant (Ki ) value for paritaprevir vs EE on average was 20 μm and was consistent with a competitive inhibition mechanism. The ratio of in-vivo maximum plasma concentration of paritaprevir to in-vitro Ki was <0.1. CONCLUSIONS:
Paritaprevir is an in-vitro inhibitor of UGT 1A1. However, the in-vitro Ki value relative to maximum clinical plasma concentrations is below the threshold to trigger a recommendation for pharmacokinetic drug interaction studies.
|
Authors | Novera Alam, Mia G Angeli, David J Greenblatt |
Journal | The Journal of pharmacy and pharmacology
(J Pharm Pharmacol)
Vol. 69
Issue 12
Pg. 1794-1801
(Dec 2017)
ISSN: 2042-7158 [Electronic] England |
PMID | 28990653
(Publication Type: Comparative Study, Journal Article)
|
Copyright | © 2017 Royal Pharmaceutical Society. |
Chemical References |
- Antiviral Agents
- Cyclopropanes
- Enzyme Inhibitors
- Lactams, Macrocyclic
- Macrocyclic Compounds
- Sulfonamides
- Ethinyl Estradiol
- Proline
- UGT1A1 enzyme
- Glucuronosyltransferase
- paritaprevir
- Probenecid
|
Topics |
- Adolescent
- Adult
- Aged
- Antiviral Agents
(pharmacokinetics, pharmacology)
- Child
- Child, Preschool
- Cyclopropanes
- Drug Interactions
- Enzyme Inhibitors
(pharmacology)
- Ethinyl Estradiol
(metabolism)
- Glucuronosyltransferase
(antagonists & inhibitors)
- Humans
- Lactams, Macrocyclic
- Macrocyclic Compounds
(pharmacokinetics, pharmacology)
- Male
- Microsomes, Liver
(drug effects, enzymology)
- Middle Aged
- Probenecid
(pharmacology)
- Proline
(analogs & derivatives)
- Sulfonamides
- Young Adult
|