Kidney Week

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

• Pharmacokinetics, Pharmacodynamics, Pharmacogenomics
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

• 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics

Authors

• Watanabe, Hiroshi, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto, Japan

Hiroshi Watanabe,

• Sugimoto, Ryusei, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto, Japan

Ryusei Sugimoto,

• Fukagawa, Masafumi, Tokai University School of Medicine, Isehara, KANAGAWA, Japan

Masafumi Fukagawa,

• Maruyama, Toru, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto, Japan

Toru Maruyama,

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.