| As pharmacists, our primary goal is to insure that every patient receives the most effective and safe dose of a given drug. In order to achieve this goal, we must gain an understanding of alterations in drug metabolism and transport, which drive many of the pharmacokinetic phenomena associated with altered physiologic states. Cellular signaling initiated through the interaction of peptides, termed cytokines, with their receptors is believed to mediate changes in drug handling during inflammation. Only through understanding the impact of cytokines on drug metabolism and transport will it be possible to predict altered pharmacokinetics in a given patient. The studies described herein further our knowledge of the important role that cytokines play in modulating drug metabolism and transport in vivo. The initial study (Chapter IV) provides evidence that stimulation of an acute cytokine response through low dose endotoxin administration can alter the metabolism and renal transport of a probe substrate in man. Further, individual changes observed in renal transport are shown to correlate with the extent of the inflammatory cytokine response as assessed by changes in NF-κB activation in peripheral blood mononuclear cells. Studies presented in Chapters V and VI demonstrate that endogenous signaling by the inflammatory cytokine TNFα differentially modulates the induction of cytochrome P450 (P450) enzymes by the classic inducers phenobarbital and clofibrate. A recent report of elevated TNFα levels in patients with Alzheimer's disease (AD), suggests that unobserved alterations in drug pharmacokinetics may be present in AD. In order to test this hypothesis, and to provide support for future human studies, differences in P450 activity between AD transgenic mice and their wild-type mice were characterized (Chapter VII). Further studies (Chapter VIII), demonstrate that alterations in P450 activity occur gradually with age and may be mediated by elevated levels of the amyloid-beta 1-42 peptide in AD transgenic mice. In summary, the studies presented herein demonstrate that inflammation and TNFα can have profound effects on drug metabolism and disposition in vivo, which could potentially lead to altered pharmacokinetics in man. Additionally, studies in mouse models of AD, a disease associated with inflammatory cytokine alterations, suggests that P450 associated drug metabolism and drug pharmacokinetics may be altered in AD patients. |
