Clinical relevance of post-transplant pharmacodynamic analysis of cyclosporine in renal transplantation.

Although therapeutic drug monitoring based on blood concentration has been widely implemented in transplant recipients treated with immunosuppressive agents, clinical adverse events such as rejection, infection or drug-induced toxicity caused by inappropriate dosage cannot be completely controlled. Development of an effective assay for optimized immunosuppression would be desirable, which can potentially lead to personalized medicine in renal transplantation. Cyclosporine (CSA) pharmacodynamic analysis using carboxyfluorescein diacetate succinimidyl ester (CFSE)-based T cell proliferation assay was examined in 66 kidney transplant recipients before and after transplantation. Two parameters, the 50% inhibitory concentration (IC50) and the percentage of T-cell proliferation values at the lower plateau (bottom), were compared with clinical events. A significant relation in CSA pharmacodynamic parameters was observed between pre- and post-transplantation. Analysis of the association between clinical outcomes and pharmacodynamic parameters in post-transplant samples demonstrated the following findings: (i) cytomegalovirus (CMV)/varicella zoster virus (VZV) reactivation and CSA-induced nephrotoxicity were significantly associated with high sensitivity to CSA (low bottom or low IC50), (ii) acute T cell-mediated rejection (ATMR) was significantly related to low sensitivity to CSA (high bottom), and (iii) de novo human leukocyte antigen (HLA) antibody production was associated with lower bottom and IC50 values, although the elucidation of those mechanisms is still in progress. It was suggested that CSA pharmacodynamics applied at post-transplantation would be useful for optimizing immunosuppressive therapy.

Short communication: lack of correlation between UGT1A1*6, *28 genotypes, and plasma raltegravir concentrations in Japanese HIV type 1-infected patients.

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.

[In-vitro study of the drug interactions between Miglitol, an alpha-glucosidase inhibitor, and adsorbents].

The interactions between miglitol, an alpha-glucosidase inhibitor, and six adsorbents (carbon spheres, cholestyramine, colestimide, sevelamer hydrochloride, calcium polystyrene sulfonate, and sodium polystyrene sulfonate) were investigated in vitro. Miglitol corresponding to the minimum dose and adsorbents corresponding to the maximum dose were incubated at 37 degrees C for 180 min in solutions of pH 1.2 (gastric pH condition) and pH 6.8 (enteric pH condition), with and without the presence of carbohydrates, which were added to observe the effects on food adsorption. The adsorption ratio of miglitol to carbon spheres was 13.6% and 0% in pH 1.2 solution and 86.4% and 5.0% in pH 6.8 solution without and with the presence of carbohydrates, respectively. Thus, the adsorption ratio was higher in pH 6.8 solution. Adsorption of miglitol to calcium polystyrene sulfonate was nearly the same, 15.0-21.9%, at both pH. The adsorption ratio of miglitol to sodium polystyrene sulfonate was 43.4% and 45.5%, respectively, in pH 1.2 solution without and with carbohydrates. In the pH 6.8 solutions, however, the respective adsorption ratios were low (5.2% and 11.3%). Miglitol did not adsorb to cholestyramine, sevelamer hydrochloride or colestimide under any pH condition examined. The above results suggest that miglitol adsorbs to carbon spheres and polystyrene sulfonic acid cation exchange resins. However, considering that miglitol is taken just before eating and thus exists in gastointestinal fluids together with food, and that the site of its effect is the upper small intestine, the interactions between miglitol and these adsorbents will most likely not be a problem.

Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport.

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.

Valproic acid increases biliary copper excretion in the rat.

The effect of valproic acid (VPA) on the copper absorption and disposition in rat small intestine was investigated using an in situ recirculating perfusion method. Following addition of VPA (20 mg) to the perfusion of 30 ml of 0.9% sodium chloride solution (2 microg/ml copper as CuSO(4)) there were no significant differences in copper decline during the perfusion. The absorption rate constant of copper (k(a)) which was estimated from the copper decline in the perfusion was unchanged without and with VPA (0.19+/-0.02 vs. 0.17+/-0.03 1/h). These results indicate that VPA does not have an effect on copper absorption from the intestine. We also assessed biliary copper excretion by measuring bile flow and biliary copper concentrations. Addition of VPA markedly increased bile flow by 47% for the first hour of bile collection and 91% for the second hour and the biliary copper excretion closely followed the increase in bile flow (without VPA: 0.93+/-0.15 vs. with VPA: 1.44+/-0.21 mg for the first and without VPA: 0.98+/-0.13 mg vs. with VPA: 1.98+/-0.22 mg for the second hour of bile collection). The total mean value for the biliary copper excretion was increased by 79%. The serum VPA concentration after the perfusion was 31.1+/-3.2 microg/ml. This high excretion of copper induced by VPA into the bile may upset the homeostatic balance of copper and cause the abnormalities of serum copper concentration. Based on the present studies, we should pay attention to copper levels in patients with VPA treatment.