| Autor: |
Wong H; Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California 94080, USA. wong.harvey@gene.com, Theil FP, Cui Y, Marsters JC Jr, Khojasteh SC, Vernillet L, La H, Song X, Wang H, Morinello EJ, Deng Y, Hop CE |
| Jazyk: |
angličtina |
| Zdroj: |
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2010 Jul; Vol. 38 (7), pp. 1029-38. Date of Electronic Publication: 2010 Apr 20. |
| DOI: |
10.1124/dmd.110.032680 |
| Abstrakt: |
Factors determining the pharmacokinetics of 2-chloro-N-(4-chloro-3-(pyridine-2-yl)phenyl)-4-(methylsulfonyl)benzamide (GDC-0449) were investigated using preclinical studies and physiologically based pharmacokinetic (PBPK) modeling. Multiple-dose studies where dogs were given twice-daily oral doses of either 7.5 or 25 mg/kg GDC-0449 showed less than dose-proportional increases in exposure on day 1. At steady state, exposures were comparable between the two dose groups. Oral administration of activated charcoal to dogs receiving oral or intravenous GDC-0449 (25 mg) showed a more rapid decrease in plasma concentrations, suggesting that the concentration gradient driving intestinal membrane permeation was reversible. The biliary clearance of GDC-0449 in dogs was low (0.04 ml/min/kg) and did not account for the majority of the estimated systemic clearance (approximately 19% of systemic clearance). Likewise, in vitro studies using sandwich-cultured human hepatocytes showed negligible biliary excretion. The effect of particle size on oral absorption was shown in a single-dose study where 150 mg of GDC-0449 of two particle sizes was administered. An oral PBPK model was used to investigate mechanisms determining the oral pharmacokinetics of GDC-0449. The overall oral absorption of GDC-0449 appears to depend on the interplay between the dissolution and intestinal membrane permeation processes. A unique feature of GDC-0449 distinguishing it from other Biopharmaceutical Classification System II compounds was that incorporation of the effects of solubility rate-limited absorption and nonsink permeation on the intestinal membrane permeation process was necessary to describe its pharmacokinetic behavior. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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