PIII‐79

BACKGROUND P‐glycoprotein (P‐gp), an ABC transporter, is expressed in normal tissues such as the heart. Domperidone, a P‐gp substrate, is associated with a block of voltage‐gated cardiac K + channels and drug‐induced Long QT syndrome. The aim of our study was to determine effects of verapamil (also a P‐gp substrate) pre‐treatment on distribution of 3 H‐domperidone to the heart and other tissues. METHODS Male Hartley guinea pigs were pre‐treated or not with a single intraperitoneal injection of verapamil (11.6 mg/kg) 2h prior the intraperitoneal injection of 3 H‐domperidone (2.5 mg/kg). Animals were sacrificed at 9 different timepoints up to 7h after the administration of 3 H‐domperidone. Tissues were excised and processed by liquid scintillation spectroscopy to determine radioactivity levels. RESULTS Higher AUC values were generally observed in heart structures (11 to 15%) and other tissues (up to 19%) of animals pre‐treated with verapamil compared to control animals. The highest differences were observed in prostate gland, testes, heart and liver, tissues known to express P‐gp. CONCLUSIONS The higher levels of 3 H‐domperidone in heart from verapamil pre‐treated guinea pigs would suggest a higher incidence of cardiotoxicities such as drug‐induced Long QT syndrome when domperidone is co‐administered with another P‐gp substrate. The impairment of P‐gp activities by verapamil pre‐treatment suggests that caution is advisable when prescribing domperidone with another P‐gp substrate. Clinical Pharmacology & Therapeutics (2005) 79 , P80–P80; doi: 10.1016/j.clpt.2005.12.287