Kinetics of d-tubocurarine disposition and pharmacologic response in rats |
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Authors: | Akira Morino Kazunori Kitamura Kazunori Katayama Masawo Kakemi Tamotsu Koizumi |
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Affiliation: | (1) Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, 930 Toyama, Japan;(2) Present address: Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinoshomonguchi-cho, Kisshoin, Minami-ku, 601 Kyoto, Japan |
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Abstract: | After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of3H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses 0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range 0.15 mg/kg.This work was presented at the First Japanese-American Symposium on Pharmacokinetics and Biopharmaceutics, Tokyo, July 1981, which was held in memory of Dr. Sidney Riegelman. |
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Keywords: | d-tubocurarine pharmacokinetics pharmacodynamics multicompartrnent model Hill equation plasma tibialis anterior muscle protein binding rats |
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