Cyclosporin metabolism by the gastrointestinal mucosa.

Abstract

The intestinal mucosal metabolism of the immunosuppressant cyclosporin (CsA) has been studied in vitro using the Ussing chamber technique. Histologically normal colon was obtained from six patients undergoing resections. The mucosal sheets were mounted between two perspex chambers. Three hours after addition of [3H]-CsA (0.2 uCi; 10 FLM) to the mucosal chamber, more than 90% of the radioactivity was present in that chamber. Metabolite analysis, by high performance liquid chromatography, indicated that 77.6 ± 9.2% (mean ± s.d.) of the drug present was CsA, 9.9 ± 4.4% and 8.7 ± 4.7% were the oxidative metabolites M17 and M21 respectively (metabolites identified by co-chromatography with authentic standards). Total metabolite production in tissues from the six individuals was variable (10.1-30.6% at 3 h) and increased over the time period of the study. A different pattern of metabolism was obtained from a single sample of gastric mucosa. More than 20% of CsA was metabolised although neither M17 nor M21 were detected. The results of this study suggest that the gut wall is involved in the first pass metabolism of CsA in vivo and that this could be a contributory factor to the poor systemic availability of CsA seen in some patients.

Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale drug-delivery systems

“…[19][20][21] The factors impeding the absorption of CyA include the narrow absorption window in the upper gut, P-glycoprotein efflux from enterocytes, and extensive presystemic metabolism in the wall and liver. 22,23 To date, how to improve CyA's in vivo performance has been a widespread concern, and various oral drug carriers have emerged, such as solid dispersion, 19,24,25 nanosuspension, 26 liposomes, 27 lipid NPs, 28 self-microemulsifying drug-delivery system (SMEDDS), 16 and PLGA NPs. 17 Although each of these were reported to significantly increase CyA oral bioavailability, only the SMEDDS of CyA (Sandimmun Neoral ® ) was High-performance liquid chromatography (HPLC)-grade methanol and acetonitrile were purchased from Tedia (Carson City, CA, USA).…”

The Pharmacokinetic Profile of Freeze-dried Cyclosporine A-Eudragit S100 Nanoparticle Formulation in Dogs

“…However, it is known that the oral bioavailability of CyA is usually very low with a high inter-and intra-patient variability due to the poor absorption, which is related to the relatively high molecular weight, very high lipophilicity and extensive metabolism. Moreover, the major limitation of CyA remains hepatotoxicity, nephrotoxicity, central nervous system toxicity and gastroenteric reaction ( Cohen et al, 1984; Thomson et al, 1991;Tjai et al, 1991).Most studies have been performed to decrease the above mentioned side effects and increase the therapeutic efficacy of CyA. CyA-nanoparticles have been used extensively as a formulation for improving the bioavailability of poorly water-soluble drugs due to its small particle size and unique uptake mechanisms.…”

Cyclosporine A-nanoparticles enhance the therapeutic benefit of adipose tissue- derived stem cell transplantation in a swine myocardial infarction model

“…However, the severe adverse effects of long-term CsA usage have limited its success in clinical use. 6 It is reasonable to manipulate CsA to improve drug targeting, lower toxicity, and increase efficiency and convenience.…”

“…However, serious side effects are associated with CsA clinical use, including renal toxicity, 6 which dictates changes in therapeutic strategies, such as the development of alternative and less toxic CsA formulations with controlled drug release and targeting of CsA to the heart. Building on the successful targeting drug delivery system of cancer chemotherapy, the present work prepared and characterized CsA incorporated into CsA-NP.…”