Relationship of UGT1A1 inhibition and occurrence of hyperbilirubinemia by HIV protease inhibitors
HIV Inhibitor | Dose | Fu2 | Cmax — Cmin2 | Cmax,u — Cmin,u2 | Ki | Cmax/Ki — Cmin/Kid | Cmax,u/Ki — Cmin,u/Kid | Observed Hyperbilirubinemiae |
|---|---|---|---|---|---|---|---|---|
| mg | μM | μM | μM | |||||
| Atazanavir | 400 q.i.d. | 0.135 | 6.28-0.312 | 0.847-0.042 | 1.9 | 3.31-0.16 | 0.45-0.02 | Yes, some patients |
| Indinavir | 800 t.i.d. | 0.40 | 12.6-0.293 | 5.04-0.117 | 47.9 | 0.26-0.06 | 0.11-0.002 | Yes, some patients |
| Saquinavir | 600 t.i.d. | <0.02 | 0.29-0.060 | 0.006-0.001 | 6.52c | 0.04-0.01 | 0-0 | No |
| Lopinavira | 400 b.i.d. | <0.02 | 15.3-8.75 | 0.306-0.175 | 4.3c | 3.56-2.03 | 0.07-0.04 | No |
| Ritonavir | 600 t.i.d. | <0.02 | 15.6-5.15 | 0.312-0.103 | 9.5c | 1.64-0.54 | 0.03-0.01 | No |
| Nelfinavir | 750 t.i.d. | <0.02 | 6.70-2.44 | 0.134-0.049 | 5.5c | 1.22-0.44 | 0.02-0.01 | No |
b Plasma protein unbound drug fraction Fu, maximum plasma drug concentration (Cmax), and plasma drug concentration at trough (Cmin) values were from literature reports (Flexner, 2000; de Maat et al., 2003; Goldsmith and Perry, 2003). Free drug concentrations were calculated by multiplying drug concentrations by Fu.
↵ a The combination of lopinavir and ritonavir (400 mg/100 mg) was approved for clinical use (Hurst and Faulds, 2000).
↵ c Ki was estimated based on Ki = 1/2 × IC50 when [S] = Km, assuming a competitive inhibition.
↵ d AUCi/AUC = 1 + [I]/Ki (Ito et al., 1998); [I] = Cmax, Cmin, Cmax,u, or Cmin,u for prediction.
↵ e Elevated unconjugated bilirubin was associated with administration of atazanavir and indinavir in some patients (Flexner, 2000; Goldsmith and Perry, 2003).