title: Effect of cimetidine on pentamidine induced hyperglycemia in rats.
abstract: The antiprotozoal agent pentamidine, used for the treatment of Pneumocystis jirovecii pneumonia (PCP), is known to cause abnormalities in blood glucose homeostasis, such as hypoglycemia and hyperglycemia. Pentamidine has been reported to be a substrate of organic cation transporter 1 (OCT1). We investigated the combination effects of cimetidine, an OCT1 inhibitor, on the pharmacokinetics of pentamidine and on pentamidine-induced hyperglycemia. Pentamidine was infused intravenously to rats for 20 min at a dose of 7.5 or 15 mg/kg and serum samples were obtained periodically. The serum concentration of glucose did not change significantly after pentamidine infusion at 7.5mg/kg, while it increased with pentamidine at 15 mg/kg, and the maximal concentration of glucose was 167 ± 36 mg/dl, 30 min after the start of pentamidine infusion. Cimetidine (50mg/kg) enhanced the pentamidine-induced elevation of glucose concentration and the maximal concentration of glucose was 208 ± 33 mg/dl in the pentamidine 15 mg/kg treated group. Cimetidine combination significantly reduced total body clearance of pentamidine and increased pentamidine concentrations in the liver, kidneys, and lungs. A significant correlation was found between changes in serum glucose concentrations and serum concentrations of pentamidine 30 min after the start of pentamidine infusion. These results suggest that the hyperglycemic effect of pentamidine is dependent on the concentration of pentamidine and can be enhanced by cimetidine combination.
authors.affiliation: Department of Pharmacy, University Hospital of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Arino
authors.forename: Seiji
authors.initials: S
authors.lastname: Karakawa
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ishiwata
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagata
authors.forename: Masato
authors.initials: M
authors.lastname: Yasuhara
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001786:Blood Glucose / Q000032:analysis; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D002927:Cimetidine / Q000494:pharmacology*; D006632:Histamine / Q000097:blood; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D010419:Pentamidine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000981:Antiprotozoal Agents; D001786:Blood Glucose; D050482:Catecholamine Plasma Membrane Transport Proteins; D006635:Histamine H2 Antagonists; D007328:Insulin; C493212:Slc22a1 protein, rat; D010419:Pentamidine; D002927:Cimetidine; D006632:Histamine