tcsc0432 Ritonavir

Ritonavir is an inhibitor of HIV protease used to treat HIV infection and AIDS.

In Vitro: Ritonavir is an inhibitor of CYP3A4 mediated testosterone 6β-hydroxylation with mean K_i of 19 nM and also inhibits tolbutamide hydroxylation with IC₅₀ of 4.2 μM^[1]. Ritonavir is found to be a potent inhibitor of CYP3A-mediated biotransformations (nifedipine oxidation with IC₅₀ of 0.07 mM, 17alpha-ethynylestradiol 2-hydroxylation with IC₅₀ of 2 mM; terfenadine hydroxylation with IC₅₀ of 0.14 mM). Ritonavir is also an inhibitor of the reactions mediated by CYP2D6 (IC₅₀=2.5 mM) and CYP2C9/10 (IC₅₀=8.0 mM)^[2]. Ritonavir results in an increase in cell viability in uninfected human PBMC cultures. Ritonavir markedly decreases the susceptibility of PBMCs to apoptosis correlated with lower levels of caspase-1 expression, decreases in annexin V staining, and reduces caspase-3 activity in uninfected human PBMC cultures. Ritonavir inhibits induction of tumor necrosis factor (TNF) production by PBMCs and monocytes in a time- and dose-dependent manner at nontoxic concentrations^[3]. Ritonavir inhibits p-glycoprotein-mediated extrusion of saquinavir with an IC₅₀ of 0.2 μM, indicating a high affinity of ritonavir for p-glycoprotein^[4]. Ritonavir inhibits human liver microsomal metabolism of ABT-378 potently with K_i of 13 nM. Ritonavir combined with ABT-378 (at 3:1 and 29:1 ratios) inhibits CYP3A (IC₅₀=1.1 and 4.6 μM), albeit less potently than Ritonavir (IC₅₀=0.14 μM)^[5].