Abstract
We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a Km of 26.5 μM and a Vmax of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC50 values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.
Highlights
IntroductionRosmarinic acid (Figure 1) is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid and a major phytochemical found in various dietary and medicinal herbs such as rosemary (Rosmarinus officinalis), perilla (Perilla frutescens), basil (Ocimum basilicum), Mellisa officinalis, Origanum vulgare, Salvia officinalis, and Satureja hortensis [1]
We investigated the effect of rosmarinic acid on the pharmacokinetics of furosemide, a substrate for OAT1 and OAT3 [24,25], and valsartan, a substrate for OATP1B1 and
This suggested that active secretion mediated by the renal transport system can be involved in the urinary excretion of rosmarinic acid
Summary
Rosmarinic acid (Figure 1) is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid and a major phytochemical found in various dietary and medicinal herbs such as rosemary (Rosmarinus officinalis), perilla (Perilla frutescens), basil (Ocimum basilicum), Mellisa officinalis, Origanum vulgare, Salvia officinalis, and Satureja hortensis [1]. It is widely used for dietary ingredients and has been reported to possess various biological activities including antioxidative, anti-inflammatory, anti-apoptotic, and anti-bacterial activities [2]. Noguchishinohara et al [9] reported the pharmacokinetics of rosmarinic acid in humans following
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