5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 8–11 July 2003, Le Meridien Montparnasse, Paris, France

IN VITRO/IN VIVO CORRELATIONS AND OTHER MISADVENTURES IN PHARMACOLOGY

Antiviral Therapy 2003; 8:L2 (abstract P4.)

CW Flexner
Departments of Medicine, Pharmacology, and International Health, Johns Hopkins University, Baltimore, MD, USA

We use a variety of in vitro model systems to predict the in vivo pharmacology of new drugs or better understand an observed drug effect, often a new toxicity. These models may provide scientific insight that cannot be gained elsewhere. However, extrapolating from in vitro models to whole organisms is hazardous, and usually requires some in vivo validation. For example, hepatic microsomes and cell lines are useful in predicting major routes for human drug metabolism, but are less successful in predicting pharmacokinetic inhibition or induction interactions. The latter problem is most likely due, in part, to failure of some cells to express the requisite orphan nuclear receptor PXR, which regulates expression of drug metabolizing enzymes and transport proteins. Our recent work showing selective induction of apoptosis by HIV protease inhibitors in human preadipocytes and intestinal cell lines provides an intriguing possible mechanism for lipodystrophy and gastrointestinal toxicity, but still requires clinical correlation. A consistent problem in using in vitro models is the static drug exposure of laboratory experiments versus the dynamic exposures produced in intact organisms. One possible solution involves a permeable hollow fibre cartridge system designed to mimic human pharmacokinetics. This system produces concentration–time curves identical to those seen in patients, and can also be used to assess protein binding effects. This model predicted the value of less frequent dosing of zidovudine and other antiretroviral nucelosides. This and other potential solutions to the problem of in vitro/in vivo correlation will be discussed.

Presenting author: CW Flexner

2003-07-08
P4

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