Organ perfusion and mass spectrometry: a timely merger for drug development.
Organ perfusion techniques bridge the methodological gap between in vivo studies on the one hand and in vitro studies on the other. In drug candidate selection and subsequent development the differences between these systems should be considered carefully in study design, as one approach may be more suitable than the other depending on the question(s) being asked and, in particular, how the data will be used. This article is not concerned with the mechanics, the surgery or composition of perfusates as there are numerous reviews/books covering these aspects. Instead, using perfused gut, liver, lung, kidney and brain as examples, the emphasis is on the usefulness (or otherwise) of the data generated with respect to drug absorption, metabolism, pharmacokinetics (PK) and the factors which affect these parameters. Perfusion systems are not difficult to set up but do require 'high maintenance' for routine use. For this reason they have been used sparingly by the pharmaceutical industry mainly for problem solving or mechanistic studies. The latter part of this article shows how simultaneous dosing of numerous compounds followed by multiple--component analysis using LC/MS/MS has proved to be an effective way to improve the throughput of absorption, pharmacokinetics and metabolism screening ex vivo.
Curtis
C Gerald
CG
Bowman Research Ltd, Newport, Gwent, UK.
Chien
Ben
B
Bar-Or
David
D
Ramu
Kumar
K
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008954:Models, Biological; D009928:Organ Specificity; D010477:Perfusion / Q000379:methods; D010599:Pharmacokinetics