Numerous clinical reports have documented an increase in trough blood concentrations of cyclosporine in transplant recipients treated concomitantly with ketoconazole. The objective of this study was to elucidate the mechanism(s) underlying the cyclosporine-ketoconazole interaction using a choledochoureterostomy dog model. Five male beagle dogs received a 4 mg/kg, i.v. bolus dose of cyclosporine either alone or on day seven of a 10-day, 13 mg/kg/day, oral dosing regimen of ketoconazole. Blood samples were collected prior to and at predetermined times for 60 hrs after the cyclosporine dose, while the bile/urine mixture was collected quantitatively for 96 hours after the cyclosporine dose. Ketoconazole decreased the systemic clearance of cyclosporine from 7.0 ml/min/kg to 2.5 ml/min/kg. The terminal disposition rate constant was also decreased significantly from 0.0794 to 0.0354 hrs-1. Ketoconazole caused no significant changes in cyclosporine steady state volume of distribution, or plasma unbound fraction. Ketoconazole did not significantly alter the excretion of cyclosporine and various cyclosporine metabolites in the bile/urine mixture. Inhibition of hepatic drug metabolizing enzymes appears to be the primary reason for the ketoconazole induced elevation in cyclosporine concentration.
The in vitro metabolism of tacrolimus (TAC, FK 506) was investigated in the liver microsomes prepared from normal rats as well as rats treated with dexamethasone (DEX) and rifampin (RIF). The rate of tacrolimus metabolism was similar in control and RIF treated rat liver microsomes, whereas it significantly increased in microsomes obtained from dexamethasone treated rats. Seven different possible metabolites were identified in the microsomal preparations from rats treated with rifampin or dexamethasone whereas the microsomes from the control rats failed to produce the mono-demethylated and monohydroxylated metabolite of TAC (TAC+2, m/z = 805.5). There was an apparent difference in the amount of individual metabolites formed in different groups. This indicates quantitative differences in the induction of cytochrome P450 3A, an enzyme sub family known to be primarily responsible for tacrolimus metabolism. Lack of induction of tacrolimus metabolism by rifampin can be attributed to the lack of effect of rifampin in inducing cytochrome P450 3A in rats.
THE DEVELOPMENT of cyclosporine (CyA) as a novel immunosuppressive agent has dramatically advanced orthotopic liver transplantation (OLT). The use of CyA in pediatrie OLT patients has been hindered by a lack of information concerning the drug’s pharmacokinetics in children and the interpretation of blood concentrations during therapy. OLT should have a major effect on CyA’s absorption, distribution, metabolism, and excretion since CyA is fat-soluble, highly protein-bound, completely metabolized, and excreted in the bile.1 Presently, two methods are available for measuring CyA in biological fluids. The two drug assays available produce different results2 and measure different components of CyA activity. The primary objectives of this study were (1) to examine the bioavailability and pharmacokinetics of CyA in children receiving OLTs and (2) to examine the relationship between drug assay results and the biochemical and clinical status of the pediatrie OLT patients.
555 The inclusion of older transplant recipients and donors may affect drug metabolism following orthotopic liver transplantation (OLTx). The purpose of this study was to characterize the activity of five drug-metabolizing cytochrome P450 enzymes (CYP) in liver transplant patients in comparison to healthy normal subjects. Methods: Stable tacrolimus-treated OLTx patients were given a 5-drug cocktail with the following agents: chlorzoxazone (CYP2E1), mephenytoin (CYP2C19), caffeine (CYP1A2), debrisoquine (CYP2D6), and dapsone (CYP3A). Drug/metabolite concentrations were determined in blood or urine and used to calculate standard measures of enzyme activity. A healthy group of normal subjects aged 67-91 years were studied as controls. The median age of the OLTx patients was 51 years (range 25-72 years), so the group was assessed as Old-OLTx (>51 years) and Young-OLTx (≤ 51 years). Studies were also divided to those greater than and less than 30 days postoperatively. Results: The measures of enzyme activity are listed below: (Table)TableDifferences were only observed in the early postoperative period, and demonstrated induced 2E1 and depressed 2C19 and 3A4. After 30 days, no significant differences between the Old-OLTx and the old normal subjects were observed. Donor age (15-68 years) by itself did not explain variability in CYP enzyme activity. However, in the Old-OLTx >30 day group, the two highest values for CYP2C19 (approximately 1.5 X mean) were for 15 and 16 year old donors. Conclusions: (1) stable older OLTx patients metabolize drugs similarly to older normal subjects, (2) Old-OLTx patients have similar postoperative changes in metabolism as Young-OLTx patients, and (3) donor age may selectively influence drug metabolizing enzymes and warrants further study.
