The impact of pretransplant T-cell sensitivity testing using carboxylfluorescein diacetate succinimidyl ester (CFSE)-based flow cytometry was studied in 32 patients with chronic renal failure. There was considerable interindividual variation in the inhibitory effects of cyclosporine (CSA), tacrolimus (TAC), and prednisolone (PRD) but only a small amount of interindividual variation for mycophenolic acid (MPA). Patients with high sensitivity to CSA tended to experience viral reactivation. In addition to post-transplant blood-level monitoring, pretransplant pharmacodynamics could provide useful information on optimal and safe immunosuppressive therapy.
Raltegravir is metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). We analyzed the genotypes of UGT1A1 (*6, *27, and *28) and their contribution to plasma raltegravir concentrations in 56 Japanese HIV-1-infected patients in the National Hospital Organization Nagoya Medical Center of Japan. Among the 56 patients, the UGT1A1 genotype in two patients was *6 homozygote. Heterozygous variants were found in 13 patients for *6 and in 11 patients for *28, while all of the patients were found to carry wild-type sequences at the position corresponding to the *27 allele. Plasma raltegravir concentration of a male patient with *6 homozygote (0.53 μg/ml) was modestly higher than that of patients with wild type (0.12 μg/ml) or *6 heterozygote (0.16 μg/ml). Another female patient with the *6 homozygote had a low plasma raltegravir concentration (0.03 μg/ml). Patients heterozygous for the *6 or *28 allele did not display significantly different plasma raltegravir concentrations compared to patients homozygous for the respective wild-type allele. Thus, in the present study, we showed that heterozygous reduced-function *6 and *28 alleles appear to have no significant effect on plasma raltegravir concentrations in Japanese HIV-1-infected patients. However, variability in raltegravir concentration and small patient population precluded a correlation between UGT1A1*6 homozygosity and plasma raltegravir concentration. To clarify the contribution of UGT1A1*6 or *28 polymorphisms to plasma raltegravir concentrations, further investigations on larger subject populations are required.
Carvedilol is often used to treat hypertension and for prophylaxis in vascular sclerosis in renal transplant recipients, who require concomitant treatment with ciclosporin. However, there are few reports regarding the pharmacokinetic interactions between carvedilol and ciclosporin. We have investigated the potential effects of carvedilol on the pharmacokinetics of ciclosporin, and examined the inhibitory effects of carvedilol on P-glycoprotein-mediated transcellular transport using Caco2 cells. Ciclosporin alone or with carvedilol was orally or intravenously administered to rats. The oral administration of carvedilol (10 mg kg(-1)) with ciclosporin (10 mg kg(-1)) increased the whole blood concentration of ciclosporin. When ciclosporin (3 mg kg(-1)) was intravenously administered with carvedilol (3 mg kg(-1)), there was no difference in the whole blood ciclosporin concentration between administration with and without carvedilol. Co-administration with carvedilol increased ciclosporin bioavailability from 33% to 70%. In Caco2 cells, carvedilol caused a concentration-dependent increase in the intracellular accumulation of ciclosporin, and its effect was comparable with that of verapamil. Carvedilol considerably raised the concentration of ciclosporin in the blood and this interaction was associated with the absorption phase of ciclosporin. This interaction was caused by the inhibition of P-glycoprotein-mediated transport by carvedilol in the intestine.
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