Abstract: SA-PO655

Parathyroid Hormone Contributes to the Down-Regulation of Cytochrome P450 3A through the cAMP/PI3K/Akt Signaling Pathway in Secondary Hyperparathyroidism

Session Information

Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

  • 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics

Authors

  • Watanabe, Hiroshi, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto, Japan
  • Sugimoto, Ryusei, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto, Japan
  • Fukagawa, Masafumi, Tokai University School of Medicine, Isehara, KANAGAWA, Japan
  • Maruyama, Toru, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto, Japan
Background

Although it is reported that humoral factors, such as uremic toxins, may contribute to the change of extra-renal drug clearance observed in CKD, the details have not been clarified. We investigated the role of parathyroid hormone (PTH) in the change of extra-renal clearance.

Methods

Secondary hyperparathyroidism (SHPT) model rats were created by feeding a high phosphorus diet to the 5/6 renal nephrectomy rats. In vitro experiments were performed using rat primary hepatocyte and Caco-2 cells.

Results

In rats with SHPT, hepatic and intestinal expression of CYP3A was down-regulated. Pharmacokinetic study using midazolam, a probe of CYP3A metabolism, showed that area under the curve (AUC) after oral administration increased about 8 times in the SHPT group compared to the sham group. These changes were suppressed by the administration of cinacalcet, a calcimimetic PTH suppressor, suggesting PTH contributes to the down-regulation of CYP3A. Using rat primary hepatocytes and Caco-2 cells, PTH (1-34) treatment decreased the expression of CYP3A proteins. The data supported the results obtained from SHPT rats. In Caco-2 cells, PTH (1-34) down-regulated mRNA expression of CYP3A but inactive PTH derivative (13-34) did not, suggesting that the action of PTH (1-34) occurs via PTH receptor. In addition, 8-Br-cAMP significantly reduced mRNA expression of CYP3A. Inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation.

Conclusion

PTH down-regulates hepatic and intestinal CYP3A expression through cAMP/PI3K/Akt pathways, following the elevation of intracellular cAMP via PTH receptor. Such effects of PTH can be prevented by a cinacalcet treatment.