Physiological mechanism-based analysis of dose-dependent gastrointestinal absorption of L-carnitine in rats
✍ Scribed by Kenji Matsuda; Hiroaki Yuasa; Jun Watanabe
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 190 KB
- Volume
- 19
- Category
- Article
- ISSN
- 0142-2782
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✦ Synopsis
We evaluated the dose-dependent (saturable) gastrointestinal absorption of L-carnitine, a lipid-lowering agent, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)-in vivo correlation in intestinal transport. The intestinal absorption rate constant (k a ), which was estimated by the analysis of gastrointestinal disposition, decreased markedly from 0.1061 to 0.0042 min -1 when the dose was increased from 0.05 mmol rat -1 (low dose) to 100 mmol rat -1 (high dose). The dose-dependence in k a was attributable to the saturability of intestinal transport that, in the perfused intestine, was similar to the saturability in k a . At the high dose, the apparent absorption rate constant (k a % ) of 0.0021 min -1 , which was estimated by the analysis of plasma concentrations after oral administration, was an order of magnitude smaller than the gastric emptying rate constant (k g ) of 0.059 min -1 and comparable with the k a of 0.0042 min -1 , suggesting that the gastrointestinal absorption of L-carnitine is absorption-limited in the intestine. At the low dose, where intestinal L-carnitine absorption was far more efficient, the k a % of 0.0172 min -1 was smaller than the k a of 0.1061 min -1 and closer to the k g of 0.072 min -1 , suggesting that apparent absorption was retarded by gastric emptying which is less efficient than intestinal absorption. This shift in the rate-determining process with an increase in dose explains the less marked dose dependence in k a % compared with k a . The bioavailability decreased from 100 to 42% with an increase in dose. This could be accounted for quantitatively by a reduction in the fraction absorbed (F a,oral ) due to a reduction in k a , assuming first-order absorption during the transit time of T si through the small intestine (F a,oral =1exp(-k a • T si )). Thus, using L-carnitine as a model, this study has successfully demonstrated that the saturability in gastrointestinal absorption can be correlated with the intestinal transport in a quantitative and mechanism-based manner. This should be of help not only for developing more efficient oral L-carnitine delivery strategies, taking advantage of in vitro (in situ) information about the intestinal transport mechanism, but also for establishing a more generally applicable in vitro (in situ)-in vivo correlation in gastrointestinal absorption.