tacrolimus and Diarrhea--Infantile

We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcineurin Inhibitors; Child, Preschool; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diarrhea, Infantile; Epithelial Cells; Female; Humans; Immunosuppressive Agents; Infant; Lipopolysaccharides; Liver Transplantation; Living Donors; Male; Rats; Tacrolimus

Topics: Biopsy; Diarrhea, Infantile; Humans; Immunosuppressive Agents; Infant, Newborn; Intestinal Diseases; Intestinal Mucosa; Intestines; Liver Transplantation; Male; Microscopy, Electron; Microvilli; Parenteral Nutrition, Total; Tacrolimus

Two infants with biliary atresia who exhibited three-fold increased trough levels of tacrolimus and required reduced doses during episodes of acute infantile diarrhea within 5 months of liver transplantation are described. The cause of the increase was not explained simply by hemoconcentration as a result of significant loss of extracellular fluid during these episodes. It does highlight an important issue: that of the continuing need to carefully monitor the trough levels of tacrolimus in such infants.

Topics: Acute Disease; Biliary Atresia; Diarrhea, Infantile; Female; Humans; Immunosuppressive Agents; Infant; Jaundice; Liver Transplantation; Portoenterostomy, Hepatic; Tacrolimus

We hereby report our experience with an index case of a pediatric liver transplant patient in whom FK506 administration was associated with the development of proximal renal tubular acidosis (RTA), as well the prevalence of acidosis and renal dysfunction in all pediatric liver transplant patients in our institution followed long term during a 6-year period. Data were grouped according to immunosuppressant regime: cyclosporine (CsA) only, FK506 only, or CsA with conversion to FK506. A 23-month-old female treated with FK506 after orthotopic liver transplantation (OLT) performed 15 months earlier presented with a 1-wk history of fever, watery diarrhea and metabolic acidosis. Although the acidosis did not improve following correction of her hydration status, administration of oral bicarbonate was effective. Discontinuation of this therapy resulted in acidosis. Since other indirect measurements of renal tubular function were normal, the patient was judged to have an isolated proximal RTA. In our group of pediatric liver transplant patients converted from CsA to FK506, FK506 administration was associated with a decline in serum bicarbonate (19 +/- 1 vs. 16 +/- 1 mEq/l, p < 0.02); neither blood urea nitrogen nor serum creatinine differed between the two groups. The number of rejection episodes/patient/month was comparable, allowing clinically relevant comparison of relative drug nephrotoxicities. We conclude that proximal RTA may be a relatively common treatable complication of FK506 administration in children.

Topics: Acidosis, Renal Tubular; Administration, Oral; Bicarbonates; Blood Urea Nitrogen; Child; Creatinine; Cyclosporine; Diarrhea, Infantile; Female; Fluid Therapy; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Kidney Diseases; Kidney Tubules, Proximal; Liver Transplantation; Longitudinal Studies; Prevalence; Tacrolimus