HIV protease, CYP3A4
Ritonavir is a Cytochrome P450 3A and Protease Inhibitor; Also inhibits Cytochrome P450 2D6, P-Glycoprotein and induces Cytochrome P450 2C19, Cytochrome P450 1A2, Cytochrome P450 2C9, Cytochrome P450 2B6 and UDP Glucuronosyltransferases.
Target: HIV protease, CYP3A4
Chemical name: (3S,4S,6S,9S)-4-hydroxy-12-methyl-9-(1-methylethyl)-13-[2-(1-methylethyl)-4-thiazolyl]-8,11-dioxo-3,6-bis(phenylmethyl)-2,7,10,12-Tetraazatridecanoic acid 5-thiazolylmethyl ester
Formula: C37H48N6O5S2
Molecular weight: 720.94
Purity: 99.92 %
Solubility: 144 mg/mL (DMSO), 20 mg/mL (ethanol)
Size: 10mg
Storage: 3 years -20°C powder, 2 years -80°C in solvent
In vitro:
Ritonavir is a very potent inhibitor of CYP3A4 mediated testosterone 6β-hydroxylation with mean Ki 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 found to be 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 Ki 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]
References:
[1] Eagling VA, et al. Br J Clin Pharmacol, 1997, 44(2), 190-194.
[2] Kumar GN, et al. J Pharmacol Exp Ther, 1996, 277(1), 423-431.
[3] Weichold FF, et al. J Hum Virol, 1999, 2(5), 261-269.
[4] Drewe J, et al. Biochem Pharmacol, 1999, 57(10), 1147-1152.
[5] Kumar GN, et al. Drug Metab Dispos, 1999, 27(8), 902-908.