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Metoclopramide disposition in normal and uremic humans Wright, Matthew Rowland


Metoclopramide (MCP) is a potent antinauseant/ antiemetic and gastrointestinal motility modifier. MCP finds clinical use in a wide variety of situations and is administered on both an acute and chronic basis. This thesis examines the pharmacokinetics of MCP in both normal, healthy volunteers and in uremic subjects on a maintenance hemodialysis program. Specifically, in the normal, healthy volunteers, the dose-linearity, and absolute and relative bioavailabilities are examined. In the uremics, the effects of chronic renal failure on MCP kinetics, the removal of MCP by hemodialysis, and the effects of hemodialysis on MCP kinetics are examined. Based on early reports, the pharmacokinetics of MCP were claimed to be dose-dependent and the absolute bioavailability extremely variable. However, many of these early studies suffered from methodological problems which limit the credibility of their findings. Based on a four-way crossover study involving six normal, healthy volunteers we find, in contrast to previous results, that the kinetics of MCP are linear over the dose range of 5 -20 mg, the absolute bioavailability is 76 ± 38 %, and the relative bioavailability of a solution dosage form vs the tablet dosage form is approximately 1. Although renal clearance accounts for only about 20 % of the total body clearance of MCP in normals, uremia has been shown to substantially alter MCP kinetics in both rat and man. There appears to be at least a two-fold decrease in total body clearance with an attendent, proportional increase in elimination half-life and insignificant change in volume of distribution. Hemodialysis is relatively ineffective in clearing MCP from the body and this inefficiency is probably related to the relatively large volume of distribution of MCP. Hemodialysis also has no effects on the apparent kinetic parameters following its termination. In addition, results from a single patient who received a kidney transplant show that the renewed renal function is accompanied by an apparent reversion of all kinetic parameters to within normal limits within 15 days of transplantation.

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