Biochemistry, physiology and drug metabolism--implications regarding the role of the lungs in drug disposition

Blood flow and its distribution may influence the functioning of drug metabolizing enzymes in vivo, and also determine the degree to which various organs participate in the metabolic clearance of agents from the body. 'Physiological' pharmacokinetic modeling suggests that in some situations the lung, because of its greater blood flow, may have a significant role in metabolic drug clearance in vivo, despite its low content of drug-metabolizing enzymes relative to the liver. For example, rat liver has much greater microsomal benzoa]pyrene (BP) hydroxylase (AHH) activity than lung, both in control rats and in rats pretreated with the enzyme inducer, 3-methylcholanthrene (3MC). However, studies using AHH enzyme kinetics, as well as studies in isolated perfused organs and in vivo, indicate that the lungs' contribution to total body metabolic clearance of BP is substantial despite the lungs' relatively low AHH activity compared to liver. Studies with 5-hydroxytryptamine similarly indicate that the lung is important in the metabolic disposition of this amine. These results emphasize that the role of an organ in metabolic drug disposition in vivo cannot be predicted directly from enzyme activity in that organ. By accounting for both biochemical and physiological influences, useful predictions regarding drug disposition may be made for normal and diseased individuals.