Comparison of Cyclosporin A Absorption from LCT and MCT Solutions following Intrajejunal Administration in Conscious Dogs

Abstract

Absorption from the intestine of cyclosporin A (CsA), dissolved in either a medium-chain (MCT) or a long-chain triglyceride (LCT) solution, was investigated in a chronic dog model. Following intrajejunal administration of 20 mg of CsA/kg of body weight, absorption, judged by the portalvenous appearance of CsA, was determined by measuring whole blood CsA concentrations in the portalvenous and arterial blood and the portalvenous flow. Appearance of CsA from LCT commenced earlier and attained significantly higher mean peak values (+/- SEM) in the portalvenous blood (2557 +/- 436 ng/mL) than from MCT (274 +/- 80 ng/mL). Portalvenous concentrations of CsA were always higher than arterial concentrations for both LCT and MCT, suggesting that CsA is transported by portalvenous blood following uptake from the gut. Absorption of CsA, measured over 300 min, was 10 times higher with LCT (9.96 +/- 2.00%) than with MCT (0.95 +/- 0.21%). This significant difference is believed to result from the formation of mixed micelles which occurs during digestion of LCT but not MCT.

Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: Studies with halofantrine

“…On first examination, the data appear contradictory and some reveal better performance for MCT 21,22 whilst others suggest a preference for LCT 13,[23][24][25] (see Ref. 14 for a review). However, closer examination reveals that the two studies performed using either fasted healthy humans or dogs 13,24,25 showed, in agreement with our results, higher drug exposure after administration of poorly water-soluble compounds in LCT solution formulations. All the other studies (including all those where MCT was shown to be most preferable) were conducted in rats.…”

Lipid-Based Formulations for Oral Administration: Opportunities for Bioavailability Enhancement and Lipoprotein Targeting of Lipophilic Drugs

“…Cyclosporin (CY) is a cyclic undecapeptide with potent immunosuppressive activity, which is lipophilic (log P 2.92) and poorly water soluble. Behrens et al subsequently proposed that the improved intestinal absorption of CY from LCT vehicles was a function of the improved capacity of the products of LCT digestion to intercalate into intestinal mixed micelles (62). Subsequent studies confirmed these data and showed that the absorption of cyclosporin was significantly improved after administration in a lipid vehicle made up of glycerides of long-chain fatty acids compared with MCT (60).…”

Bioavailability of oral drug formulations and methods for its improvement

“…Кишечная лимфатическая система -уникальный высокоёмкий путь транспорта для некоторых липофильных лекарств через клетку, особенно при одновременном введении с липидами [22]. Транспорт в лимфу показан для многих высоко липофильных лекарств и ксенобиотиков: производных тестостерона, пробукола, циклоспорина, ретиноидов, ликопина и др [22,40]. Скорость такого транспорта невелика, так как скорость движения лимфы ~ в 500 раз ниже скорости кровотока в воротной вене.…”