Pregnane X Receptor Agonists Impair Postprandial Glucose Tolerance

We conducted a randomized, open, placebo‐controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration–time curves (AUCincr) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C‐peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUCincr during OGTT was significantly increased in rats after 4‐day treatment with pregnenolone 16α‐carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance. Clinical Pharmacology & Therapeutics (2013); 93 6, 556–563. doi:10.1038/clpt.2013.48