Evaluation of the potential inhibition effect of Paritaprevir on UGT 1A1 enzyme activity using human liver microsomes
Alam, Novera.
2017
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Abstract: Abstract The treatment landscape of chronic hepatitis C (HCV) has
changed substantially over the last decade with the introduction of direct-acting antiviral
drugs, creating more options to treat the disease. However, the importance of clinically
relevant drug-drug interaction remains a challenge. Paritaprevir has been a successful
candidate when used in a multidrug regimen for the t... read morereatment of HCV. However, its metabolic
pathway overlaps with that of many other drugs, resulting in increased exposure of the
substrate to the enzymes. A previous clinical study has shown that oral contraceptives
containing 0.035mg of ethinyl estradiol (EE) when given with Viekirex
(Ombitasvir/paritaprevir/ritonavir) increased the ethinyl estradiol Cmax by 16%, AUC 6% and
Cmin 12%, which is a small change. Paritaprevir Cmax, AUC, and Cmin decreased by 30%, 34%,
and 13% respectively. This can result in treatment failure or in some cases a health risk
issue. Co-administration of EE with Viekirex is contraindicated due to increase ALT level
in blood. The objective of this study was to evaluate the inhibitory effect of paritaprevir
on UGT 1A1 isoforms to identify the mechanism of inhibition of ethinyl estradiol
metabolism. We also wanted to relate the findings to different pharmacokinetic models to
evaluate whether the interaction was clinically significant. An in vitro study was done in
human liver microsomes to evaluate biotransformation of EE into its glucuronide metabolites
(EE-3-O-G, EE-17-O-G). The inhibition of metabolite formation rates by paritaprevir was
evaluated using different kinetic models. EE-3-O-G, the major metabolite, demonstrated
substrate inhibition characteristics. Paritaprevir inhibited EE with an IC50 of 14.5±1.02
µM. Probenecid was used as a positive control inhibitor with, an IC50 1.4±1.6 mM. The
time-dependent inhibition study, in which the inhibitor was pre-and not pre-exposed to the
enzyme prior to substrate addition, showed a very similar inhibitory concentration. The
inhibition constant (ki) value for paritaprevir on average was 20.6µM (≥ IC50). The pattern
of inhibition indicated that the inhibition was reversible with competitive
characteristics. The ratio of in vivo maximum concentration of paritaprevir to in vitro
([I]/ki) was 0.01658, indicating that a clinically significant drug-drug interaction is
unlikely.
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisors: David Greenblatt, and Margery Beinfeld.
Keyword: Pharmacology.read less - ID:
- m039kh17c
- Component ID:
- tufts:22743
- To Cite:
- DCA Citation Guide EndNote
