Physiological mechanism-based analysis of dose-dependent gastrointestinal absorption of L-carnitine in rats.
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 (ka), 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 micromol rat(-1) (low dose) to 100 micromol rat(-1) (high dose). The dose-dependence in ka was attributable to the saturability of intestinal transport that, in the perfused intestine, was similar to the saturability in ka. 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 (kg) of 0.059 min(-1) and comparable with the ka 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 ka of 0.1061 min(-1) and closer to the kg 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 ka. 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 ka, assuming first-order absorption during the transit time of T(si) through the small intestine (F(a,oral) = 1 - exp(-ka x 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.
Matsuda
K
K
Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Yuasa
H
H
Watanabe
J
J
D000465:Algorithms; D000818:Animals; D001646:Bile / Q000378:metabolism; D002331:Carnitine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar
D000960:Hypolipidemic Agents; D002331:Carnitine