Induction of the hepatic cytochrome P450-3A4 system and intestinal P-glycoprotein by rifampicin is difficult to be overcomed by other drugs and require substantial increase in tacrolimus dose when given concurrently. Chronic diarrhea is known to precipitate tacrolimus toxicity irrespective of its cause in renal transplant recipients.
A 24 years old lady had chronic renal failure due to membranous glomerulonephritis. She had kidney transplantation in 1988 complicated by chronic rejection, and a second renal transplant in 1993 which is functioning well. She was maintained on prednisolone, azathioprine and tacrolimus. She has close relatives infected with tuberculosis. She was started on isoniazide prophylaxis in April 2002 and tacrolimus was maintained on therapeutic levels. She had chronic anemia, fever, night sweating, nausea, vomiting, chronic diarrhea, and loss of weight. Detailed investigations including multiple gastrointestinal biopsies didn’t conclude definite diagnoses apart from mild gastritis.She was started on antituberculous treatment in November 2002 (rifampicin, isoniazide, ethambutol, and pyrazinamide). Ethambutol was discontinued after two months. She continued to have significant symptoms requiring multiple drugs to be controlled. She was getting omeprazole 20 mg twice daily which increases tacrolimus levels via hepatic enzyme inhibitor effect. She was taking also frequent doses of antacids (which decreases rifampicin absorption) and metoclopramide (which inhibits tacrolimus metabolism and increases its absorption). She was taking other drugs such as loperamide, acetaminophen and ondasetron hydrochloride as symptomatic treatment when required. She had very high tacrolimus blood levels requiring successive dose reduction from 7mg/day up to 0.5mg every other day with rise of serum creatinine from 100 to 140umol/l. Tacrolimus was changed to low dose sirolimus in April 2003 and renal function improved to its baseline while still on rifampicin. Gastrointestinal disturbances and multiple drug administration may cause significant toxic tacrolimus blood levels even in presence of rifampicin. Combination of enzyme P450 inhibitors and low absorption of rifampicin may overcome its strong enzyme induction effect.