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Disposition of Naringenin via Glucuronidation Pathway Is Affected by Compensating Efflux Transporters of Hydrophilic Glucuronides

Haiyan XuDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, Department of Pharmaceutical Analysis, Shenyang Pharmaceutical University, Shenyang, China, 110016, and Department of Clinical Science and Administration, College of Pharmacy, University of Houston, Houston, Texas 77030Kaustubh H. KulkarniDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, Department of Pharmaceutical Analysis, Shenyang Pharmaceutical University, Shenyang, China, 110016, and Department of Clinical Science and Administration, College of Pharmacy, University of Houston, Houston, Texas 77030Rashim SinghDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, Department of Pharmaceutical Analysis, Shenyang Pharmaceutical University, Shenyang, China, 110016, and Department of Clinical Science and Administration, College of Pharmacy, University of Houston, Houston, Texas 77030Zhen YangDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, Department of Pharmaceutical Analysis, Shenyang Pharmaceutical University, Shenyang, China, 110016, and Department of Clinical Science and Administration, College of Pharmacy, University of Houston, Houston, Texas 77030Stephen W.J. WangDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, Department of Pharmaceutical Analysis, Shenyang Pharmaceutical University, Shenyang, China, 110016, and Department of Clinical Science and Administration, College of Pharmacy, University of Houston, Houston, Texas 77030Vincent H. TamDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, Department of Pharmaceutical Analysis, Shenyang Pharmaceutical University, Shenyang, China, 110016, and Department of Clinical Science and Administration, College of Pharmacy, University of Houston, Houston, Texas 77030Ming HuDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, Department of Pharmaceutical Analysis, Shenyang Pharmaceutical University, Shenyang, China, 110016, and Department of Clinical Science and Administration, College of Pharmacy, University of Houston, Houston, Texas 77030

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The purposes of this study were to investigate how efflux transporters and UDP-glucuronosyltransferases (UGT) affect the disposition of naringenin. A rat intestinal perfusion model with bile duct cannulation was used along with rat intestinal and liver microsomes. In the intestinal perfusion model, both absorption and subsequent excretion of naringenin metabolites were rapid and site-dependent (p < 0.05). Naringenin was absorbed the most in colon, and its glucuronides were excreted the most in duodenum. In metabolism studies, the intrinsic clearance value of naringenin glucuronidation was the highest in jejunum microsomes, followed by liver, ileal and colonic microsomes. The rapid metabolism in microsomes did not always translate into more efficient excretion in the rat perfusion model, however, because of presence of rate-limiting efflux transporters. When used separately, MK-571 (an inhibitor of multidrug resistance-related protein 2 or Mrp2) or dipyridamole (an inhibitor of breast cancer resistance protein or Bcrp1) did not affect excretion of naringenin glucuronides, but when used together, they significantly (p < 0.05) decreased intestinal and biliary excretion of naringenin glucuronides. In conclusion, efflux transporters Mrp2 and Bcrp1 are shown to compensate for each other and enable the intestinal excretion of flavonoid (i.e., naringenin) glucuronides.

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DOI: 10.1021/mp900013d

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