Pharmacokinetic interactions: the effect of herbal extracts and supplements on drug permeation

Abstract

The surge in popularity to treat illnesses with a more holistic approach is causing growing concern due to the increasing occurrence of adverse reactions, which are the result of interactions due to the concomitant use of herbal medicine and/or supplements with Western medicines. The modulating effects that herbal medicines and/or supplements can have on the pharmacokinetics of concomitantly administered allopathic drugs have recently captured the attention of both researchers and medical practitioners. During this study, emphasis was placed on the investigation of the potential membrane modulating effects of four selected herbal extracts (i.e. Vitis vinifera seed, Hoodia gordonii, Harpagophytum procumbens, Leonotis leonurus) and one supplement (i.e. methylsulfonylmethane) on the intestinal epithelial permeation of a model compound. The permeation modulating effects of the selected herbal extracts and supplement were evaluated with Rhodamine 123 (RH-123), which is a known substrate of the active efflux transporter, P-glycoprotein (P-gp). The bi-directional transport of RH-123 was measured in the presence and absence of the selected herbal extracts/supplement across excised pig jejunum tissues using a Sweetana-Grass diffusion chamber apparatus. Samples of 180 μl were withdrawn every 20 min over a period of 2 h. A validated fluorescence spectroscopic method on a Spectramax Paradigm® plate reader was employed to analyse the experimental samples to determine the RH-123 concentration in each sample. A Lucifer yellow (LY) transport study was performed to prove that the technique employed in mounting the excised pig jejunum tissue was not detrimental to the integrity and viability of the tissue. All transport studies were performed in triplicate at three different concentrations of each selected herbal extract and supplement. The percentage transport and apparent permeability coefficient (Papp) values were calculated from the obtained transport data in two directions. The efflux ratio (ER) values were calculated from these Papp values. Trans-epithelial electrical resistance (TEER) was measured at the onset and termination of each transport experiment using a Warner Instruments® EC-825A epithelial voltage clamp. Decreases in the TEER values were used to confirm compromising effects on the integrity of the membrane and/or to note any potential effects of the selected herbal extracts and supplement on the tight junctions. Methylsulfonylmethane (MSM) mediated a discernible increase in RH-123 transport in the secretory (i.e. basolateral-to-apical) direction, whilst a decrease in RH-123 transport was observed in the absorptive (i.e. apical-to-basolateral) direction when compared to the negative control group (i.e. RH-123 alone). This verified that MSM is adept to induce P-gp mediated efflux in a concentration dependent manner. Vitis vinifera seed extract mediated a concentration dependent increase in RH-123 transport in both directions when compared to the negative control. Vitis vinifera seed extract also caused the TEER to decrease concentration dependently in both directions, which indicated the opening of tight junctions and consequently also caused an apparent increase in RH-123 transport. Hoodia gordonii extract mediated a concentration dependent increase in RH-123 transport in the absorptive direction with a decrease in the secretory direction, which indicated that Hoodia gordonii extract may contain molecule(s) that act as P-gp efflux pump inhibitors. Harpagophytum procumbens extract demonstrated a non-concentration dependent induction of P-gp mediated efflux. Leonotis leonurus extract exhibited a concentration dependent increase in RH-123 transport in the absorptive direction but the secretory direction demonstrated an induction of P-gp related efflux upon reaching a baseline concentration. These ex vivo pharmacokinetic interactions proved that herbal medicines and supplements can have an effect on Western medicine's membrane permeation and therefore also their bioavailability and further in vivo studies should be conducted to confirm the clinical significance thereof.