In-vitro Interaction of a Novel Immunosuppressant, FK 506, and Antacids

Abstract-The effect of selected antacids on the amount ofFK 506 in solution in simulated gastric juice has been studied. FK 506 (2·5 mg) was incubated in 100 mL simulated gastric fluid (SGF) with the equivalent of 500 mg of various antacids. The addition of Mylanta and Turns resulted in 14 and 30'1., loss of FK 506, respectively, in 24 h; 98% loss was observed in 12 h in the presence of Mag-Ox; 100'Yo loss was observed in the presence of magnesium oxide powderin 2 h. The loss ofFK 506 from these solutions appears to be due to a pH mediated degradation of FK 506. The addition of aluminium hydroxide gel USP (Roxane) to the FK 506 solution resulted in a 35°;;, loss within 2 min but no further loss was noted for 24 h. indicative of adsorption ofFK 506. These results suggest that until additional in-vivo studies are carried out. it is prudent not to dose FK 506 and antacids at the same time to avoid potential interactions

Effect of bile on cyclosporin absorption in liver transplant patients.

1. We quantitated the effect of biliary diversion on cyclosporin (CyA) absorption in liver transplant patients. Multiple blood samples were obtained over one dosing interval following oral CyA administration in eight liver transplant patients before and after T-tube clamping. 2. Cyclosporin concentrations were measured by a high pressure liquid chromatographic method. 3. The mean (+/- s.d.) dose-normalized area under the blood concentration vs time curve (AUC) over a dosing interval was 5.23 (+/- 3.22) ng ml-1 h during the pre clamping period and 15.79 +/- 7.92 ng ml-1 h during the post clamping period. A significant (P less than 0.05) increase (276%) in the dose normalized AUC was observed following the T-tube clamping. 4. Analysis of bile revealed less than 1 mg (less than 1% of dose) of unchanged CyA to be eliminated in bile over 12 h. Therefore the increased CyA AUC/dose following T-tube ligation cannot be explained by enterohepatic recirculation. 5. Increased bile flow secondary to clamping of the T-tube most likely increased the absorption of CyA. Increase in CyA absorption may be due to a bile mediated increase in CyA solubility or gastrointestinal membrane permeability, or increased residence time at the site of absorption. 6. Independent of the mechanism involved, our results indicate that adjustments in CyA dosage must be made whenever external bile diversion is instituted or discontinued

Developmental pharmacokinetics of ciclosporin – a population pharmacokinetic study in paediatric renal transplant candidates

What is already known about this subjectCiclosporin is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics.It is likely that the inter- and intraindividual variability in ciclosporin pharmacokinetics and dose requirements is even larger in children than in adults as a result of variation in biological maturation status.However, data on the developmental pharmacokinetics of ciclosporin, as well as other CYP3A4 substrate drugs, in children are scarce.What this study addsAdult CYP3A4 activity seems to be reached by the age of 6–12 months, and allometrically scaled body weight is a good predictor of the hepatic clearance of ciclosporin, a CYP3A4 substrate.Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age.These conclusions were reached using a robust modelling approach (NONMEM) with rich paediatric pharmacokinetic data collected after full i.v. and p.o. profiles