Tacrolimus is an immunosuppressant used to prevent rejection of transplanted organs. It is metabolized in both the gut and the liver by the cytochrome P450 (CYP) 3A4 enzyme system and is a substrate for the P-glycoprotein (P-gp) drug efflux pump. As CYP3A4 enzymes and P-gp are present at differing concentrations throughout the gastrointestinal tract, the bioavailability of tacrolimus may be influenced by changes in gastrointestinal transit time in addition to changes in hepatic metabolism. We report the case of a pediatric renal transplant patient who experienced a three-fold increase in serum tacrolimus concentrations during an episode of gastroenteritis with chronic diarrhea.

The loop diuretics furosemide and bumetanide are frequently employed in the pediatric population for the management of fluid overload in both acute and chronic disease states. They act mainly by inhibiting sodium reabsorption in the nephron at the thick ascending limb of Henle's loop. Important pharmacokinetic differences between adults and infants include a reduced clearance and prolonged half-life, that may cause accumulation of these agents to potentially toxic levels if dosing intervals are not adjusted. Unfortunately, little is known about the time required for maturation of loop diuretic elimination in older infants, children, and adolescents. Similar to adults, limited pharmacodynamic evidence in neonates suggests that a maximally efficient diuretic dose exists. Increasing the diuretic dose beyond this maximum does not offer further benefit, but may increase the risk of toxicity. Common problems encountered in the pediatric patient as well as in adults are loop diuretic tolerance and resistance. Loop diuretic dosing strategies aimed at overcoming these phenomena include administration by continuous infusion, coadministration with albumin, and coadministration with metolazone or thiazides. This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of furosemide and bumetanide in pediatric patients. A better understanding of the clinical pharmacology of the loop diuretics should aid clinicians in the development of dosing regimens aimed at producing adequate diuresis without promoting excessive diuretic tolerance.

A 20 mg/kg loading dose should produce a concentration after the bolus dose of approximately 75 mg/L. Initial infusion should consider hepatic induction (noninduced = 1 mg/kg/h, polyanticonvulsant therapy = 2 mg/kg/h, and high-dose pentobarbital = 4 mg/kg/h). Adjustments should be based on response and serum concentrations.

Improved understanding of the dose-effect relationship for TF in children and adolescents is necessary before adequate pain control can be achieved with this delivery system.