Gender Difference in the Urinary Excretion of Organic Anions in Rats
- 1Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.K., K.K., H.K., Y.S.); and 2Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland (P.J.M.)
- Professor Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail:sugiyama{at}mol.f.u-tokyo.ac.jp
Abstract
This study was aimed at clarifying the gender differences in the urinary excretion of organic anions and the gene expression of organic anion transporters in rats. The renal clearance with regard to the plasma concentration (CLurine,p) of taurocholate, dibromosulfophthalein (DBSP), and zenarestat, all substrates and/or inhibitors of organic anion transporting polypeptide 1 (Oatp1), was much higher in female than in male rats. The following results imply that the transport system(s) for the reabsorption of zenarestat across the luminal side exhibits a gender difference: 1) the renal uptake clearance assessed by an in vivo integration plot analysis of zenarestat from the blood side does not show any clear gender differences; 2) the renal clearance with regard to the kidney concentration (CLurine,k) of zenarestat in female rats was approximately 30 times higher than in male rats; and 3) both CLurine,p and CLurine,k were increased in male rats by the coinfusion of DBSP, which is an inhibitor of organic anion transporters. Northern and Western blot analyses confirmed a previous finding that the gene expression of Oatp1, which is localized at the apical plasma membrane of the kidney, was much higher in the kidneys of male rats. Overall, a gender difference in urinary excretion is commonly observed for several organic anions, including Oatp1 substrates and inhibitors, and Oatp1 and/or transporters that have a similar substrate specificity to Oatp1 could be involved in such a phenomenon involving its substrates.
Footnotes
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DOI: 10.1124/jpet.102.033878
- Abbreviations:
- Oat
- organic anion transporter
- Oatp
- organic anion transporting polypeptide
- Oct
- organic cation transporter
- TCA
- taurocholate
- GFR
- glomerular filtration rate
- DBSP
- dibromosulfophthalein
- HPLC
- high-pressure liquid chromatography
- E217βG
- [3H]estradiol 17β-d-glucuronide
- AUC
- area under the curve
- CLtot
- total clearance
- CLurine,p
- urinary clearance with respect to plasma concentration
- CLurine,k
- urinary clearance with respect to the kidney concentration
- bp
- base pair(s)
- TBST
- Tris-buffered saline/Tween 20
- Mrp
- multidrug resistance-associated protein
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- Received February 6, 2002.
- Accepted April 8, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
