Investigation of the pharmacokinetic interactions between Hypoxis hemerocallidea and indinavir

Abstract

It has been established that phytochemicals in herbal medicines can result in pharmacokinetic interactions when co-administrated with allopathic drugs. These herb-drug pharmacokinetic interactions may lead to an increase or decrease in drug bioavailability with consequences of adverse effects or toxicity due to increased drug plasma levels or treatment failure due to decreased plasma drug levels. The relevance of research concerning pharmacokinetic interactions between herbal medicines and anti-retroviral drugs is reflected by the fact that a relatively large portion of human immunodeficiency virus (HIV) infected patients with acquired immunodeficiency syndrome (AIDS) commonly use herbal medicines to complement their highly active anti-retroviral therapy. The aim of this study was to confirm pharmacokinetic interactions that different Hypoxis hemerocallidea (African potato) materials may have on indinavir by means of in vitro transport studies as well as by means of acute and chronic in vivo bioavailability studies. The selected H. hemerocallidea test materials included a dried plant reference material, an aqueous extract and a solid oral commercial product. Bi-directional transport of indinavir across Caco-2 cell monolayers were determined in the absence and presence of the various H. hemerocallidea materials. Indinavir alone served as the negative control and the positive control consisted of verapamil, a known P-glycoprotein (P-gp) inhibitor. The transport samples obtained were analysed by a validated high performance liquid chromatography (HPLC) method. The apparent permeability coefficient (Papp) values in both transport directions and efflux ratio (ER) values were calculated. In vivo studies were conducted in male Sprague-Dawley rats which were randomly selected and divided into 9 groups. The negative control consisted of indinavir alone. Verapamil served as the positive control for efflux inhibition and ketoconazole, a known CYP3A4 inhibitor, was used as positive control for metabolism inhibition. The H. hemerocallidea materials in combination with indinavir formed the experimental groups. The acute study consisted of a single administration and the chronic study entailed daily administrations over 14 days by means of oral gavage. A validated Liquid Chromatography tandem Mass Spectrometry (LC/MS/MS) method for the analysis of indinavir was used in order to analyse the plasma samples. Relevant pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under the curve (AUC) were determined The H. hemerocallidea test materials demonstrated an inhibition of efflux of indinavir in the Caco-2 cell model. In agreement with this finding and other published findings on metabolism inhibition, an increase in indinavir bioavailability in the presence of the selected test materials was shown in vivo for both the acute and chronic studies. The commercial product had a similar increasing effect on indinavir bioavailability as the aqueous extract, while the reference plant material exhibited a higher effect on indinavir bioavailability enhancement. A higher effect on indinavir bioavailability was observed for two of the test materials during the chronic study when compared to the acute study. The selected H.hemerocallidea materials interfered with indinavir pharmacokinetics in both the in vitro and in vivo models and these effects may be attributed to inhibition of efflux transporters and enzymatic metabolism