Drug-induced QT prolongation in cirrhotic patients with transjugular intrahepatic portosystemic shunt.
OBJECTIVE
Nearly 40% of cytochrome P450 3A (CYP3A) activity is located in the small intestine. An earlier study has shown that cirrhotics with transjugular intrahepatic portosystemic shunts (TIPS) have diminished intestinal CYP3A activity. We hypothesized that oral CYP3A substrates known to prolong QT interval may cause further prolongation of the QT interval in cirrhotic patients with TIPS.


METHODS
A total of 23 patients (9 healthy controls, 6 cirrhotics without and 8 cirrhotics with TIPS) participated in a study that tested this hypothesis using erythromycin as the probe drug. Participants with cirrhosis with and without TIPS were matched for age, sex, race, BMI and etiology of liver disease. Serial electrocardiograms were obtained at baseline, after single dose of erythromycin 500 milligrams, and after 7 days of erythromycin (500 milligrams orally twice daily). QT intervals were measured in 3 consecutive beats in 3 leads and corrected QT intervals (QTc) were obtained using various correction formulae. The maximal QTc change (ΔQTc Max) after single and multiple dose administration was the primary outcome.


RESULTS
At baseline, the QTc intervals (mean±S.E) in cirrhotics with TIPS (418±6 msec) and cirrhosis (431±6 msec) were significantly higher compared with controls (388±9 msec, P=0.021). After a single dose of erythromycin, there was no significant difference among the 3 groups in ΔQTc Max (P=0.7). However, after a 7 day course, cirrhotics with TIPS developed significantly greater ΔQTc Max (179.5±67.8 msec) compared with cirrhotics (31.2±9.5 msec) and healthy controls (38.3±3.3 msec) (P=0.03).


CONCLUSIONS
This study suggests that patients with TIPS are potentially at increased risk for abnormal QT prolongation when exposed to oral CYP 3A substrates with QT prolonging effect.
Indiana University School of Medicine, Indianapolis, IN 46202-2859, USA. rvuppala@iupui.edu
Raj
R
Vuppalanchi
Ravi
R
Juluri
Marwan
M
Ghabril
Seongho
S
Kim
Nancy
N
Thong
Jude Christopher
JC
Gorski
Naga
N
Chalasani
Stephen D
SD
Hall
D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004562:Electrocardiography; D004917:Erythromycin / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000601:surgery*; D008133:Long QT Syndrome / Q000139:chemically induced*; D019168:Portasystemic Shunt, Transjugular Intrahepatic / Q000379:methods*; D012307:Risk Factors
D000900:Anti-Bacterial Agents; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A