Elimination of diflunisal as its acyl glucuronide, phenolic glucuronide and sulfate conjugates in bile-exteriorized and intact rats

1. The disposition of diflunisal (DF) was investigated in both bile‐exteriorized and intact rats given 10 and 100 mg/kg doses intravenously (i.v.). 2. In addition to the phenolic glucuronide (DPG) and acyl glucuronide (DAG) conjugates, the sulfate conjugate (DS) was found to be a major metabolite. The glucuronides were excreted preferentially in bile, whereas DS was excreted almost exclusively in urine. 3. In bile‐exteriorized animals, recoveries of DPG, DAG and DS in bile were 12.2%, 23.8%, 0.4%, respectively, and in urine, 10.3%, 5.6% and 15.2%, respectively, at the 10 mg/kg dose; and in bile, 11.3%, 41.6% and 1.0% respectively, and urine 2.9%, 1.1% and 17.0%, respectively, at the 100 mg/kg dose. 4. Total plasma clearance of DF and formation clearance of DF to DPG were reduced at the higher dose, suggesting saturation of this glucuronidation pathway. Formation clearances of DF to DAG and DS were little affected by the dose change. 5. Considerable enterohepatic recirculation of DF was apparent from the prolongation of DF and its conjugates in plasma of rats with an intact bile flow into the gut. The net metabolic effect of such cycling was enhancement of overall DS formation, from 15.6% and 18.0% of the 10 and 100 mg/kg doses, respectively, in bile‐exteriorized rats to 28.5% and 42.1% of the doses respectively, in the intact animals

A Simultaneous D-Optimal Designed Study for Population Pharmacokinetic Analyses of Mycophenolic Acid and Tacrolimus Early After Renal Transplantation86

Mycophenolic acid (MPA) and tacrolimus (TAC) are immunosuppressive agents used in combination with corticosteroids for the prevention of acute rejection after solid organ transplantation. Their pharmacokinetics (PK) show considerable unexplained intraindividual and interindividual variability, particularly in the early period after transplantation. The main objective of the present work was to design a study based on D-optimality to describe the PK of the 2 drugs with good precision and accuracy and to explain their variability by means of patients&#039; demographics, biochemical test results, and physiological characteristics. Pharmacokinetic profiles of MPA and TAC were obtained from 65 stable adult renal allograft recipients on a single occasion (ie, day 15 after transplantation). A sampling schedule was estimated based on the D-optimality criterion with the POPED software, using parameter values from previously published studies on MPA and TAC modeling early after transplantation. Subsequently, a population PK model describing MPA and TAC concentrations was developed using nonlinear mixed-effects modeling. Optimal blood-sampling times for determination of MPA and TAC concentrations were estimated to be at 0 (predose) and at 0.24, 0.64, 0.98, 1.37, 2.38, and 11 hours after oral intake of mycophenolate and TAC. The PK of MPA and TAC were best described by a 2-compartment model with first-order elimination. For MPA, the absorption was best described by a transit compartment model, whereas first-order absorption with a lag time best described TAC transfer from the gastrointestinal tract. Parameters were estimated with good precision and accuracy. While hematocrit levels and CYP3A5 genetic polymorphism significantly influenced TAC clearance, the pharmaceutical formulation and MRP2 genetic polymorphism were retained as significant covariates on MPA absorption and elimination, respectively. The prospective use of the simultaneous D-optimal design approach for MPA and TAC has allowed good estimation of MPA and TAC PK parameters in the early period after transplantation characterized by a very high unexplained variability. The influence of some relevant covariates could be shown</p