No abstract

Purpose - Carica papaya has been traditionally used worldwide in folk medicine to treat a wide range of ailments in humans, including the management of obesity and digestive disorders. However, scientific information about its potential to interact with conventional drugs is lacking. Thus, this work aimed to investigate the interference of a standardized C. papaya extract (GMP certificate) on the systemic exposure to amiodarone (a narrow therapeutic index drug) in rats. Methods - In the first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of C. papaya (1230 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in the second study, rats were pre-treated for 14 days with C. papaya (1230 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the herbal extract vehicle. Blood samples were collected before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h following amiodarone administration; in addition, at 24 h post-dose, blood and tissues (heart, liver, kidneys and lungs) were also harvested. Thereafter, the concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were determined in plasma and tissue samples employing a high-performance liquid chromatography-diode array detection method previously developed and validated. Results - In both studies was observed a delay in attaining the maximum plasma concentrations of amiodarone (tmax) in the rats treated with the extract. Nevertheless, it must be highlighted the marked increase (60-70%) of the extent of amiodarone systemic exposure (as assessed by AUC0-t and AUC0-∞) in the rats pre-treated with C. papaya comparatively with the control (vehicle) group. Conclusions – The results herein found suggest an herb-drug interaction between C. papaya extract and amiodarone, which clearly increase the drug bioavailability. To reliably assess the clinical impact of these findings appropriate human studies should be conducted.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

There is an increasing interest in the intranasal delivery of central nervous system-active drugs due to the existence of a direct nose-to-brain connection. However, poor solubility limits the amount of drug that can be administered within an aqueous solution. In the present work, the objectives were to develop an ex vivo bioconversion/permeability evaluation method and to study the ex vivo bioconversion of the hydrophilic phosphate ester prodrug fosphenytoin (FOS) to the active drug phenytoin (PHT) and their comparative nasal permeation. Bioconversion/permeability studies were performed in excised porcine nasal mucosa mounted in Ussing chambers. The physical integrity of the tissues was evaluated by measurement of the transepithelial electrical resistance (TEER). The simultaneous quantitative assay of FOS, PHT and its major metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) was developed and validated according to international guidelines using a liquid chromatography analytical method. The FOS bioconversion rate and PHT and FOS apparent permeability coefficients (Papp) were determined at different time points. FOS bioconversion was also qualitatively investigated in human nasal mucus. The developed liquid chromatography method combines a fast and inexpensive sample preparation with inactivation of the enzymatic metabolism of the prodrug during sample manipulation and storage. It was linear, precise, accurate, and presented a high analyte recovery. FOS was converted ex vivo to PHT but the metabolite HPPH was not detected. The bioconversion rate increased with FOS concentration and with time, which suggests a diffusion-limited process. FOS was also converted to its active drug by human nasal mucus. A novel mathematical data analysis method was developed to reduce the bias introduced by variable mucosal TEER in the permeability results. At comparable FOS and PHT concentrations the ln(Papp(PHT)) of both compounds showed little difference, which indicates that the use of a hydrophilic and charged prodrug did not hinder overall drug permeation. At the highest tested FOS concentration it was possible to quantify FOS in the receiver chambers, meaning that at a sufficiently high concentration the FOS permeation rate overcame its bioconversion rate. The ln(Papp(PHT)) tended to similar equilibrium values as the assay progressed, but with higher FOS concentrations that equilibrium was attained faster. Acidic pH reduced the permeability of both PHT and FOS. The developed bioconversion/permeability evaluation method will constitute an important tool to select the most promising formulations before proceeding to in vivo studies. Importantly, it allowed the demonstration of phosphatase activity and FOS bioconversion in nasal mucosa, as well as the prodrug's nasal permeation potential. Furthermore, this study demonstrates the possibility of formulating phosphate prodrugs of poorly soluble central nervous system-active drugs as a strategy to increase the solubilized drug doses administered through the nasal route.