S1589 Alcohol Promotes HIV Protease Inhibitor-Induced Hepatoxicity By Activating the ER Stress Response in Hepatocytes

Abstract

Aim: Cytochrome P450 3A is the most important drug metabolizing enzyme in humans and nearly 40% of its activity is located in the small bowel. We have previously shown that intestinal CYP3A activity is markedly diminished in cirrhotics with transjugular intrahepatic portasystemic shunts (TIPS) and this leads to markedly increased bioavailability of orally administered CYP3A substrates and may lead to adverse effects. We conducted a study to test the hypothesis that oral CYP3A substrates with QT prolonging effect cause abnormal prolongation of QT interval in cirrhotics with TIPS. Methods: 23 subjects (9 controls, 8 cirrhotics with TIPS and 6 cirrhotics without TIPS) participated in this study. Subjects with cirrhosis and TIPSS were matched for age, gender, race and BMI. The mean age ± SD was 52 ± 9 years, 9 females and 6 African American. Oral erythromycin (ERY), a CYP3A substrate known to prolong QT interval in humans, was administered to test the relationship between diminished small bowel CYP3A activity and QT prolongation by oral medications. It was dosed at 500 mg PO BID for 7 days. EKGs (n=32) were obtained from each subject at baseline and after administration of ERY on day 1 and day 7 at scheduled intervals (over 24 hours) on each study day. QT intervals were measured in 3 consecutive beats in two leads and corrected QT interval (QTc) was obtained by fredericia correction and simple regression analysis. Primary outcome measure is maximal QTc change (QTc Max δ) after ERY administration on day 1 and day 7 in comparison to pre-drug administration baseline. The changes in QTc are compared among the three patient groups using ANOVA according to day 1 and day 7. Results: There was no statistically significant difference among the three groups in QTc Max δ following the first dose of ERY (p=0.8) on day 1. However, cirrhotics with TIPS had significantly greater QTc Max δ than other two groups following 7-days of oral ERY administration (p= 0.0271), irrespective of correction formula. Summary: Cirrhotic Patients with TIPS had significantly greater prolongation in QTc following multiple doses of erythromycin than cirrhotics without TIPS. Conclusion: Cirrhotics with TIPS are more prone for adverse events such QT prolongation by oral medications that are metabolized by small bowel CYP3A. The maximal QTc change (mean± SE) (QTc Max δ) milliseconds in each group on day 1 and on day 7 of oral erythromycin 500 mg twice daily.