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Drug Metabolism and Disposition Fast Forward
First published on April 21, 2008; DOI: 10.1124/dmd.108.020917

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Received for publication February 7, 2008.
Revised April 17, 2008.
Accepted for publication April 17, 2008.

Rate limiting steps in hepatic drug clearance: comparison of hepatocellular uptake and metabolism with microsomal metabolism of saquinavir, nelfinavir and ritonavir

Alison Parker 1 J Brian Houston 1*

1 University of Manchester

* Address correspondence to: E-mail: brian.houston{at}manchester.ac.uk

Abstract

Abstract The intrinsic metabolic clearance of saquinavir, nelfinavir and ritonavir was determined over a range of concentrations (0.02 - 20 µM) in both rat liver microsomes and fresh isolated rat hepatocytes in suspension. Clearance values were found to be concentration dependent for both systems and at low concentrations microsomal clearance was much greater (7 to 14-fold) than in hepatocytes. Kinetic parameters showed substantially lower microsomal Km values (5-42 nM) compared to suspended rat hepatocytes (34-270 nM) but similar scaled Vmax values 2-26 nmol/min/g liver. In the absence of metabolism (achieved by pre-treating hepatocytes with a mechanism-based inhibitor of cytochrome P450), saquinavir, nelfinavir and ritonavir were actively and rapidly taken up into hepatocytes (cell:medium concentration ratios of 306-3352) and intracellular unbound drug concentrations between 5 and 12-fold higher than extracellular unbound concentrations were achieved. Comparison of the rate of uptake into hepatocytes with the rate of metabolism in hepatocytes and microsomes indicates that the former is the rate limiting step at low concentrations. The rate of metabolism saturates at lower concentrations (100 to 400-fold) than the rate of uptake, hence at higher concentrations metabolic rate-limited clearance occurs. In conclusion, the clearance of saquinavir, nelfinavir and ritonavir is extremely rapid and it is proposed that in the case of hepatocytes, and by inference in vivo, the rate of transport limits the clearance of these three drugs.


Key words: drug transport, hepatic transport, hepatic uptake, hepatocytes, in vitro-in vivo prediction, in vitro-in vivo scaling, isolated hepatocytes, microsomes, permeability


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A. Poirier, T. Lave, R. Portmann, M.-E. Brun, F. Senner, M. Kansy, H.-P. Grimm, and C. Funk
Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model
Drug Metab. Dispos., December 1, 2008; 36(12): 2434 - 2444.
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