Drug disposition in the burn patient is a complex function of continuously-changing postburn pathophysiology and treatment measures. Very little information is available describing the absorption, distribution, and clearance of hepatically-cleared drugs in burn patients. From our previous studies and from the limited literature reports, it is apparent that the distribution and clearance of hepatically-cleared drugs are altered postburn. Both the quantity and quality of the information available (from our group and from others) limit the presentation a unified, definitive interpretation of postburn alterations in hepatic drug clearance. Our overall objective is to provide a unified perspective on the hepatic clearance of drugs in burn patients. From our previous studies of the clearance of meperidine, lidocaine, and indocyanine green in burn patients, we have formed the hypothesis that drugs which display blood-flow-limited hepatic clearance in normal individuals, do not necessarily display blood- flow-limited hepatic clearance in burn patients. We further hypothesize that postburn alterations in blood drug binding and in hepatic intrinsic free drug clearance will tend to, at least partially, counterbalance the postburn increase in hepatic blood flow. We will use a carefully designed, powerful, and definitive protocol to test our hypothesis within the context of the venous- equilibration model for hepatic drug clearance. We will characterize hepatic clearances, renal clearances, and drug metabolism patterns of lidocaine (following oral and intravenous (tracer) administration) and of antipyrine (following oral administration) administered simultaneously to burn patients at three postburn times (acute, convalescent, and recovered) and in control subjects. Lidocaine will represent flow-limited drugs and antipyrine will represent capacity-limited drugs. In addition, we will characterize each burn patient physiologically by estimating hepatic blood flow and plasma volume (with indocyanine green), total body water volume (with antipyrine), and glomerular filtration rate (creatinine clearance). Importantly, we wish to test models for hepatic drug clearance under the relatively unique condition of markedly increased hepatic blood flow, a condition under which these models have rarely and insufficiently been tested. Ultimately, we wish to impact postburn oral and intravenous dosing of hepatically-cleared drugs, in an attempt to improve burn patient care.
NIH ExPorter
NIH ExPorter