Table 3.
Physicochemical and in vitro pharmacokinetic parameters of ritonavir
| Parameter | Value | References |
|---|---|---|
| Physicochemical | ||
| Molecular weight | 720.95 g mol−1 | Pubchem [57] |
| Log Po:w | 4.3 | Simcyp compound library |
| Compound type | Monoprotic base | |
| pKa | 2 | Simcyp compound library |
| Blood:plasma ratio | 0.587 | Simcyp compound library |
| Fraction unbound in plasma | 0.02 | http://www.drugbank.ca/drugs/DB00503 [58] |
| Main plasma binding protein | AGP | |
| Absorption | ||
| Absorption model | First-order absorption | |
| Fraction absorbed | 1 | Simcyp compound library |
| k a (1 h−1) | 0.24 | Simcyp compound library |
| Distribution | ||
| Distribution model | Minimal PBPK model | |
| V ss (L kg−1) | 0.41 | Simcyp compound library |
| Metabolism/elimination | ||
| Clearance type | In vivo clearance | |
| CLpo (L h−1) | 16 non-pregnant; 20 pregnant | Product characteristics Norvir [21], Colbers et al. [22] |
| CLr (L h−1) | 0.32 | |
| Interaction CYP | ||
| CYP2C9 K i (µM) | 4 (F u,mic 0.29) | |
| CYP2D6 K i (µM) | 10 (F u,mic 0.29) | |
| CYP3A4 K i (µM) | 0.03 (F u,mic 0.976) | Determined |
| CYP3A4 K app (µM) | 0.1 (F u,mic 0.91) | Kaspera et al. [25] |
| CYP3A4 K inact (1 h−1) | 0.32 (F u,mic 0.91) | Kaspera et al. [25] |
| Interaction transporters | ||
| ABCB1 (P-gp) K i (µM) | 0.2 (F u,inc 0.233) | Drewe et al. [27] |
| Pooled basolateral uptakea K i (µM) | 2.5 (F u,inc 1) | Annaert et al. [28] |
AGP α1-acid glycoprotein, ABCB1 ATP-binding cassette, subfamily B, member 1, CL po clearance after oral administration, CL r renal clearance, CYP cytochrome P450, F u ,inc fraction of unbound drug in the in vitro hepatocyte incubation, F u ,mic fraction of unbound drug in the in vitro microsomal incubation (calculated), k a absorption rate constant, K app concentration of mechanism-based inhibitor associated with half-maximal inactivation rate, K i concentration of inhibitor that supports half-maximal inhibition, K inact inactivation rate of the enzyme, PBPK physiologically based pharmacokinetic, P-gp P-glycoprotein, pKa acid dissociation constant, Po:w Partition coefficient octanol:water, V ss volume of distribution at steady state
aBased on reported K i for organic anion transporting polypeptide 1B3 (2.5 µM)