Substrate | In Vivo Parameters | CLint,ha | |||||||
---|---|---|---|---|---|---|---|---|---|
fup | Rb | Intravenous Plasma Clearancea | n | Oral Plasma Clearancea | n | Intravenous | Oral | Predictedb | |
ml/min/kg | ml/min/kg | ml/min/kg | |||||||
Alfentanil | 0.086 | 0.63 | 4.19 (3.93, 4.46) | 4 | 11.4 (10.7, 12.2) | 4 | 71.8 | 73.9 | 116 (55, 176) |
Alprazolamc | 0.29 | 0.85 | 0.76 (0.71, 0.82) | 2 | 0.99 (0.90, 1.10) | 14 | 2.76 | 3.22 | 7.3 |
Atorvastatin | 0.02 | 0.55 | 8.93 | 1 | 226 (211, 241) | 7 | 2,070 | 2,710 | 50.8 (26.0, 75.5) |
Buspirone | 0.05 | 0.81 | 28.3 | 1 | 1,170 (797, 1670) | 14 | 3,020 | 4,920 | 229 (178, 281) |
Cisapride | 0.02 | 1.0 | —d | — | 7.85 (7.08, 8.69) | 4 | — | 216 | 256 (186, 325) |
Cyclosporine | 0.068 | 1.36 | 3.99e (3.50, 4.59) | 7 | 12.3e,f (9.92, 14.9) | 8 | 110 | 97g | 66.4 (30.6, 102) |
Cyclosporine | 0.068 | 1.36 | 3.99e (3.50, 4.59) | 7 | 25.4e,h (20.4, 31.0) | 7 | 110 | 201g | 66.4 (30.6, 102) |
Felodipine | 0.004 | 0.70 | 11.9 (11.4, 12.4) | 4 | 110 (88, 137) | 11 | 17,020 | 12,300 | 1,700 (1,080, 2,330) |
Indinavir | 0.36 | 0.84i | 18.4 | 1 | 14.2 (13.1, 15.3) | 6 | 440 | 30.4j | 498 (342, 653) |
Lovastatin | 0.043 | 0.57k | — | — | 329 (293, 368) | 5 | — | 535 | 4,100 (2,340, 5,852) |
Methadone | 0.21 | 0.75 | 1.66 (1.49, 1.85) | 5 | 2.13 (1.94, 2.34) | 6 | 7.48 | 7.03 | 19.1 (13.6, 24.7) |
Midazolam | 0.031 | 0.55 | 6.16 (5.64, 6.72) | 30 | 24.2 (20.5, 28.5) | 14 | 440 | 402 | 367 (209, 525) |
Nifedipine | 0.044 | 0.67 | 7.55 (7.00, 8.14) | 3 | 15.6 (12.0, 17.5) | 14 | 378 | 245 | 255 (212, 298) |
Nisoldipine | 0.003 | 1.0l | 14.4 (13.2, 15.6) | 4 | 319 (280, 361) | 5 | 15,900 | 11,700 | 5,990 (3,630, 8,350) |
Quinidinec | 0.26 | 0.87 | 3.86 (3.42, 4.35) | 2 | 5.64 (5.18, 6.13) | 3 | 11.6 | 15.0 | 7.4 |
Repaglinide | 0.015 | 0.60 | 7.76 | 1 | 13.7 (12.8, 14.8) | 21 | 1,380 | 815 | 110 (77.3, 142) |
Rifabutin | 0.29 | 0.60 | 3.46 | 1 | 16.2 (12.8, 20.5) | 8 | 16.6 | 11.5 | 68.1 (42.4, 93.7) |
Saquinavir | 0.028 | 0.74 | 12.9 (10.3, 16.0) | 2 | 3,440 | 1 | 2,920 | 6,640g | 6,390 (4,410, 8,360) |
Sildenafil | 0.04 | 0.64 | 8.97 | 1 | 9.42 (8.72, 10.2) | 4 | 694 | 127 | 139 (113, 166) |
Simvastatin | 0.06 | 0.57i | — | — | 387 (317, 469) | 18 | — | 903 | 6,080 (4,730, 7420) |
Tacrolimus | 0.13 | 35 | 0.64e (0.57, 0.73) | 4 | 4.93e (4.09, 5.83) | 8 | 179 | 186 | 892 (313, 1,470) |
Terfenadine | 0.03 | 1.0 | — | — | 1,260 | 1 | — | 16,800 | 2,940 (2,290, 3,600) |
Trazodone | 0.07 | 1.0l | 2.14 (1.94, 2.34) | 3 | 2.27 (2.18, 2.37) | 8 | 34.1 | 26.9 | 54.9 (41.2, 68.6) |
Triazolamc | 0.10 | 0.62 | 2.94 (2.77, 3.13) | 7 | 6.36 (5.92, 6.83) | 9 | 38.2 | 47.2 | 43.7 |
Verapamil | 0.093 | 0.89 | 11.7 (11.0, 12.5) | 6 | 43.3 (39.1, 47.8) | 6 | 347 | 303 | 283 (165, 401) |
Zolpidem | 0.08 | 0.76 | 4.25 (3.96, 4.55) | 2 | 5.14 (4.33, 6.06) | 11 | 71.8 | 50.8 | 14.1 (8.54, 19.6) |
↵a Intravenous and oral clearance data represent systemic plasma clearances. Observed CLint,h values after intravenous and oral administration were calculated using eqs. 5 and 6, respectively, after plasma clearances were corrected for renal excretion and blood/plasma ratio (CLh = (CLp − CLrenal)/Rb).
↵b CLint,h predictions based on the mean in vitro clearance data from three HLM pools.
↵c CLuint data were supplemented from Galetin and Houston (2006) for alprazolam (8.46 and 0.515 μl/min/mg in HLM and HIM, respectively), quinidine (6.60 and 2.13 μl/min/mg in HLM and HIM, respectively), and triazolam (51.2 and 4.73 μl/min/mg in HLM and HIM, respectively).
↵d —, data not available or not applicable.
↵e Blood clearance data.
↵f Oral clearance of cyclosporine (Neoral).
↵g Fraction absorbed: 0.9 and 0.3 for cyclosporine and saquinavir, respectively; otherwise complete absorption was assumed.
↵h Oral clearance of cyclosporine (Sandimmune).
↵i Provided by Pfizer, Global Research and Development.
↵j Evidence for saturation in vivo (Yeh et al., 1999).
↵k Assumed to be the same as for simvastatin.
↵l Assumed to be 1.