This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Erythromycin is an antibiotic, which is used to treat various bacterial infections such as sore throat, pneumonia, and skin infections. Erythromycin is known to increase the heart rate corrected EKG QT interval (QTc) by an average of 20 msec in healthy volunteers. Patients with liver cirrhosis experience a greater baseline QTc intervals relative to non-cirrhotics and the magnitude of the prolongation is correlated with the severity of the disease. Our preliminary data showed that cirrhotics belonging to Child's class A, B, or C had a mean QTc interval of 419, 438 and 463 msecs, respectively compared to a 394 msec in healthy volunteers. Liver cirrhosis is known to reduce hepatic Cytochrome P450 3A4 (CYP3A4) enzyme activity, compared to healthy volunteers. The intestinal CYP3A4 activity is markedly diminished in cirrhotics with transjugular intrahepatic portasystemic shunts (TIPS), relative to age, gender, etiology, and Child-Pugh class matched cirrhotics without TIPS and healthy volunteers. The clearance of erythromycin is mediated in part by CYP3A4 and decreases with multiple dosing. Therefore, orally administered CYP3A substrates (such as erythromycin) that cause little prolongation of QTc in healthy subjects may cause marked QTc prolongation in patients with cirrhosis and TIPS. It previously has been shown that pharmacokinetics of erythromycin are altered in patients with cirrhosis (prolongation of half-life and decrease hepatic intrinsic clearance). This raises the possibility that orally administered erythromycin could lead to further prolongation of QTc interval in patients with cirrhosis. Therefore, we plan to conduct a prospective study to determine the effects of single dose and multiple doses of oral erythromycin on the corrected QT interval in healthy subjects, patients with cirrhosis, and patients with cirrhosis and TIPS. An electrocardiogram will be performed at regular intervals following erythromycin administration and heart rate corrected QTc interval will be calculated using method of Fridericia (QTc = QT/(RR)1/3).
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