Possible roles of intestinal P-glycoprotein and cytochrome P450 3A on the limited oral absorption of irinotecan.

OBJECTIVES: Irinotecan is a widely intravenously used drug for the treatment of certain types of solid tumours. The oral administration of irinotecan has recently been recognized as being a more effective method for the treatment than intravenous administration. However, the limited oral bioavailability of irinotecan poses a problem for its oral delivery. In this study, we report on an investigation of the mechanism responsible for the limited oral absorption of irinotecan using rats as models. METHODS: The intestinal absorption of irinotecan in the absence and presence of several compounds was examined using intestinal loop method. The pharmacokinetics of irinotecan was investigated when verapamil, an inhibitor of the P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) was pre-administered. KEY FINDINGS: The intestinal absorption of irinotecan was enhanced in the presence of verapamil, indicating that efflux by intestinal P-gp contributes to its limited oral absorption. Indeed, the oral bioavailability of irinotecan was increased when verapamil was orally pre-administered. This increased oral bioavailability was accompanied by a slight but significant decrease in the formation of a metabolite produced by the action of CYP3A. CONCLUSION: The findings presented herein suggest that intestinal efflux by P-gp is mainly and intestinal metabolism by CYP3A is partially responsible for the limited oral absorption of irinotecan.

Intestinal patches with an immobilized solid-in-oil formulation for oral protein delivery.

Oral administration of biomolecular drugs such as peptides, proteins, and DNA is an attractive delivery method because of the safety and convenience of delivery in contrast to injection administration. However, oral delivery of biomolecules has several potential barriers such as enzymatic degradation in the gastrointestinal tract and low permeability across an intestinal membrane. In this study, we proposed an intestinal patch system that included surfactant-coated insulin for oral delivery. The intestinal patches, which have mucoadhesive and drug-impermeable layers, induced sustained unidirectional insulin release toward intestinal mucosa and inhibition of insulin leakage from the patches. Moreover, the surfactant-coated insulin, which has high compatibility with cell membranes, enhanced insulin transport across the intestinal membrane. This study demonstrates that the intestinal patches might improve protein permeability in the intestinal mucosa, thereby offering an innovative therapeutic strategy.

A simple determination of mizoribine in human plasma by liquid chromatography with UV detection.

A simple liquid chromatography (LC) method was developed for determination of the therapeutic level of mizoribine in human plasma. After precipitation of plasma proteins with 6% perchloric acid, mizoribine was determined by LC with spectophotometric detection. The peak height for mizoribine was linearly related to its concentrations, which ranged from 0.09 to 3.13 microg/mL. Therefore, the limit of quantitation was considered to be 0.09 microg/mL. The accuracy was 104.96-107.37%. The intra- and interday relative standard deviation values were in the range of 1.10-3.25%. The detection limit was 0.025 microg/mL, defined as a signal-to-noise ratio of 3. The plasma concentrations of mizoribine were not related to the dosage. Because mizoribine was mainly excreted in the urine, the plasma concentrations of mizoribine might be affected by a change in renal function. Therefore, the mizoribine concentration in blood should be monitored and the dosage adjusted, depending on the condition of renal function. It was suggested that the present method may be applied well in the therapeutic drug monitoring for mizoribine.

An enteric-coated dry emulsion formulation for oral insulin delivery.

A novel oral dosage formulation of insulin consisting of a surfactant, a vegetable oil, and a pH-responsive polymer has been developed. First, a solid-in-oil (S/O) suspension containing a surfactant-insulin complex was prepared. Solid-in-oil-in-water (S/O/W) emulsions were obtained by homogenizing the S/O suspension and the aqueous solution of hydroxypropylmethylcellulose phthalate (HPMCP). A microparticulate solid emulsion formulation was successfully prepared from the S/O/W emulsions by extruding them to an acidic aqueous solution, followed by lyophilization. The insulin release from the resultant dry emulsion responded to the change in external environment simulated by gastrointestinal conditions, suggesting that the new enteric-coated dry emulsion formulation is potentially applicable for the oral delivery of peptide and protein drugs.

Effect of P-glycoprotein modulator, cyclosporin A, on the gastrointestinal excretion of irinotecan and its metabolite SN-38 in rats.

PURPOSE: The purpose of this work was to investigate the role of the hepatic and intestinal P-glycoprotein (P-gp) and canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2 (cMOAT/MRP2) on both biliary excretion and intestinal exsorption of irinotecan hydrochloride (CPT-11) and its metabolite, SN-38, in the lactone and carboxylate forms. Cyclosporin A (CsA) was used to modulate P-gp and cMOAT/MRP2. METHODS: The transcellular transport of CPT-11 and SN-38 was examined by using LLC-PK1 derivative cell lines transfected with murine mdrla both in the absence or in the presence of CsA. The excretions of the compounds through the biliary and intestinal membrane routes were investigated by in situ perfusion technique. RESULTS: Basolateral-to-apical transport of CPT-11 lactone in L-mdr1a cells was significantly decreased by CsA (10 microM). The transcellular transport of SN-38 lactone showed similar behaviors as those of CPT-11 lactone. The biliary excretion and the intestinal exsorption of both forms of CPT-11 and SN-38 were significantly inhibited when the drug was co-administered with CsA. CONCLUSIONS: The transports of CPT-11 and SN-38 via the biliary route seem to be essentially related with cMOAT/MRP2, whereas those of both compounds via the intestinal membrane seem to be related with P-gp.

Hypoglycemic effect of surfactant-coated insulin solubilized in a novel solid-in-oil-in-water (S/O/W) emulsion.

A novel solid-in-oil-in-water (S/O/W) emulsion for oral administration of insulin has been developed using surfactant-coated insulin. The S/O/W emulsion prepared by a shirasu porous glass (SPG) membrane provided a sharp size distribution and was stable. Leakage of insulin from the S/O/W emulsions was not observed for several days. The S/O/W emulsion showed the hypoglycemic activity for a long period after oral administration to rats.