Abstract
Changes in the disposition of estradiol 17β-d-glucuronide (E217G), a substrate of the organic anion-transporting polypeptide family (Oatp) and multidrug resistance-associated protein 2 (Mrp2), were examined in livers of male Wag/Rij rats that were injected with CC531 cells intraportally to induce metastatic tumors (n = 5) or with phosphate-buffered saline for sham-operated controls (n = 4). Multiple indicator dilution, single-pass liver perfusions revealed extremely high influx clearances of [3H]E217G (>190 ml/min) in both groups. In recirculating liver perfusions, [3H]E217G decayed monoexponentially in the reservoir perfusate, and the total (9.19 ± 1.33 versus 8.18 ± 0.94 ml/min) and biliary (4.94 ± 1.07 versus 4.60 ± 0.86 ml/min) clearances were similar in both groups (P > 0.05). The metabolic clearance of E217G was higher in the tumor group (4.60 ± 0.64 versus 3.23 ± 0.23 ml/min, P < 0.05). E23S17G, the 3-sulfate metabolite, whose identity was confirmed by mass spectrometry, appeared only in bile and not perfusate. Liver microsomal incubations of E2335S17G and [3H]estrone sulfate revealed similar sulfatase activities between the tumor and sham livers, albeit the activities were much lower for E2335S17G. Oatp1a1 and Oatp1b2 protein expression in liver membrane fragments was reduced by 42% and 38%, respectively, whereas that of cytosolic estrogen sulfotransferase (Sult1e1) was significantly increased (41%) with tumor (P < 0.05). All of the observations were captured by modeling. From modeling, we showed that reduction of the high influx clearance (546 to 283 ml/min) failed to lower the total clearance of E217G, whereas up-regulation of Sult1e1 increased the E217G sulfation clearance (2.56 to 3.69 ml/min) in livers with metastatic tumors.
Footnotes
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This work was supported by the Canadian Institute for Health Research Grant MOP 64350.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.108860.
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ABBREVIATIONS: MRP, multidrug resistance-associated protein; E217G, estradiol 17β-d-glucuronide; Oatp, rat organic anion transporting polypeptide; Mrp, rat multidrug resistance-associated protein; Bcrp, rat breast cancer resistance protein; E23S17G, estradiol 3-sulfate-17β-d glucuronide; E1, estrone; E1S, estrone 3-sulfate; KHB, Krebs-Henseleit buffer; HPLC, high performance liquid chromatography; E2, estradiol; E23G, estradiol 3-glucuronide; E23S, estradiol 3-sulfate; BSA, bovine serum albumin; Sult, rat sulfotransferase; RBC, red blood cell; Hct, hematocrit; PBS, phosphate-buffered saline; MID, multiple indicator dilution; AUC, the area under the concentration-time curve; RT, reaction time; ESI, electrospray ionization; PBPK, physiologically based pharmacokinetic.
- Received June 2, 2006.
- Accepted August 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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