Incorporation of in vitro drug metabolism data into physiologically-based pharmacokinetic models

Toxicology in Vitro : an International Journal Published in Association with BIBRA
J B Houston, D J Carlile

Abstract

The liver poses particular problems in constructing physiologically-based pharmacokinetic models since this organ is not only a distribution site for drugs/chemicals but frequently the major site of metabolism. The impact of hepatic drug metabolism in modelling is substantial and it is crucial to the success of the model that in vitro data on biotransformation be incorporated in a judicious manner. The value of in vitro/in vivo extrapolation is clearly demonstrated by considering kinetic data from incubations with freshly isolated hepatocytes. The determination of easily measurable in vitro parameters, such as V(max) and K(m), from initial rate studies and scaling to the in vivo situation by accounting for hepatocellularity provides intrinsic clearance estimates. A scaling factor of 1200 x 10(6) cells per 250 g rat has proved to be a robust parameter independent of laboratory technique and insensitive to animal pretreatment. Similar procedures can also be adopted for other in vitro systems such as hepatic microsomes and liver slices. An appropriate scaling factor for microsomal studies is the microsomal recovery index which allows for the incomplete recovery of cytochrome P-450 with standard differential centrifugation of liver...Continue Reading

References

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Citations

Jun 19, 2012·Fish Physiology and Biochemistry·Aliakbar Hedayati, Abdolreza Jahanbakhshi
Nov 11, 2010·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Zichao RaoGao Li
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Jun 23, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Chuang LuLiang-Shang Gan

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