Inhibition of Human Cytochromes P450 in vitro by Ritonavir and Cobicistat.
Hossain, Md Amin.
ritonavir, cobicistat is also a potent inhibitor of cytochrome P450 3A enzymes,
including subtype CYP3A4. Both of them have the ability to inhibit liver enzymes that
metabolize other medications used to treat HIV, like atazanavir, darunavir and
elvitegravir. Ritonavir and cobocistat have been using in highly active antiretroviral
therapy (HAART) combination for boosting activity ... read morethat suppresses HIV replication. The
mechanism of action behind the antiretroviral boosting drug is to inhibit human
cytochrome (mainly CYP450) isoforms which may lead to increase HIV antiviral drug's
plasma concentration. Primary objective of this study is to see whether ritonavir and
cobicistat inhibit any other cytochrome isoforms and to figure out what is the
inhibition mechanism of these two drugs. This paper evaluates the inhibiting effect of
ritonavir and cobicistat on different cytochrome isoforms, including CYP2B6 and CYP2C19
using an in vitro model based on human liver microsomes. Ritonavir inhibited CYP2C19 and
CYP2B6 activity with mean IC50 20.69 µM and 15.41 µM accordingly. Cobicistat
also inhibited CYP2C19 and CYP2B6 activity with mean IC50 6.45 µM and 10.17 µM
accordingly. For CYP2B6 and CYP2C19, percent control values (ritonavir and cobicistat)
for pre-incubation phase were always higher than without pre-incubation one. This
indicates that, the inhibition mechanism is not time-dependent (mechanism based) rather
time independent in this study. In summary, cytochrome isoforms (CYP2C19 and CYP2B6)
were significantly inhibited in not time-dependent manner by ritonavir and
Thesis (M.S.)--Tufts University, 2016.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisors: David Greenblatt, and Margery Beinfeld.
Keyword: Pharmacology.read less