Severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency: first case presentation showing competition for excretion via renal multidrug resistance protein 1 and organic cation transporter 2.

A 72-year-old woman with renal insufficiency who was taking oral pilsicainide (150 mg/d) complained of feeling faint 3 days after she was prescribed oral cetirizine (20 mg/d). She was found to have a wide QRS wave with bradycardia. Her symptoms were relieved by termination of pilsicainide. The plasma concentrations of both drugs were significantly increased during the coadministration, and the cetirizine concentration decreased on cessation of pilsicainide despite the fact that treatment with cetirizine was continued, which suggested that the fainting was induced by the pharmacokinetic drug interaction. A pharmacokinetic study in 6 healthy male volunteers after a single dose of either cetirizine (20 mg) or pilsicainide (50 mg), or both, found that the renal clearance of each drug was significantly decreased by the coadministration of the drugs (from 475 +/- 101 mL/min to 279 +/- 117 mL/min for pilsicainide and from 189 +/- 37 mL/min to 118 +/- 28 mL/min for cetirizine; P = .008 and .009, respectively). In vitro studies using Xenopus oocytes with microinjected human organic cation transporter 2 and renal cells transfected with human multidrug resistance protein 1 revealed that the transport of the substrates of these transporters was inhibited by either cetirizine or pilsicainide. Thus elevated concentrations of these drugs as a result of a pharmacokinetic drug-drug interaction via either human multidrug resistance protein 1 or human organic cation transporter 2 (or both) in the renal tubular cells might have caused the arrhythmia in our patient. Although cetirizine has less potential for causing arrhythmias than other histamine 1 blockers, such an interaction should be considered, especially in patients with renal insufficiency who are receiving pilsicainide.

Different effects of imidapril and enalapril on aminopeptidase P activity in the mouse trachea.

It has been reported that the incidence of angiotensin-converting enzyme (ACE) inhibitor-related dry cough is significantly less with the ACE inhibitor imidapril than with the ACE inhibitor enalapril in hypertensive patients. Bradykinin (BK) in the trachea is believed to play some role in this adverse effect. The present study was undertaken to evaluate the effects of imidapril and enalapril on the activity of aminopeptidase P (APP), one of the BK-metabolizing enzymes, in the mouse trachea. Imidapril (0.5 mg/kg) or enalapril (0.5 mg/ kg) was given orally to mice once daily for 7 days. Drug concentrations and APP activity in the trachea were determined at the end of the experiment. Active metabolites (imidaprilat and enalaprilat), but not parent drugs (imidapril and enalapril) were detected in the trachea after a repeated dose for 7 days. Tissue concentrations of imidaprilat and enalaprilat did not significantly differ. The APP activity in the trachea did not significantly change after the 7th dose of imidapril. However, the enzyme activity was significantly inhibited after the final dose of enalapril. Thus, the present study showed that enalapril, but not imidapril inhibited the airway APP activity during repeated dosing. This finding is compatible with previous reports that the incidence of dry cough is lower with imidapril than with enalapril, and with the hypothesis that the dry cough induced by ACE inhibitors may be related to accumulation of BK in the trachea.

Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein.

We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.

Case report of unchanged tacrolimus clearance in a hypoxemic pediatric liver transplant recipient with hepatopulmonary syndrome.

Reductions in hepatic oxygen supply may reduce the oxidative metabolism of drugs, including tacrolimus. We encountered a patient (2.3-year-old girl) with hypoxemia [arterial oxygen tension (PaO2) 40.9 mmHg in room air] due to hepatopulmonary syndrome who had undergone living related liver transplantation. After transplantation, tacrolimus was initially administered by continuous intravenous infusion, and her PaO2 was maintained at more than 50 mmHg [72.8+/-10.4 (SD) mmHg] by oxygen supplementation. Apparent clearance of tacrolimus (calculated as: the infusion rate of tacrolimus/blood concentration) in the patient (0.075 l/h per kg) was comparable to those of non-hypoxemic control pediatric cases (0.092+/-0.014 l/h per kg, n=7, mean age 2.2 years, PaO2 149.2+/-41.5 mmHg), except for the acute decline in the early period after transplantation. These findings suggest that the reduction in tacrolimus clearance is negligible when arterial oxygen tension is maintained at more than 50 mmHg, even in patients with hypoxemia.

Pharmacokinetic and immunosuppressive effects of tacrolimus-loaded biodegradable microspheres.

The objective of this study was to characterize the pharmacokinetics and immunosuppression of a tacrolimus-loaded biodegradable microsphere (TLBM) in rats. We prepared TLBM. DA/Slc rats were given TLBM at a dose of 1.6 mg/kg (n = 9), 2.4 mg/kg (n = 5), or 7.2 mg/kg (n = 7) tacrolimus contents by a single subcutaneous administration to achieve sustained release over a long period. DA/Slc rats were given TLBM by a single subcutaneous administration at a dose of 4.8 mg/kg (n = 6) tacrolimus contents to clarify the main site of TLBM uptake in the organs. In the rat liver transplantation model, the recipients were given TLBM at a dose of 0.16 mg/kg (n = 5), 2.4 mg/kg (n = 4), or 4.8 mg/kg (n = 5) tacrolimus contents by a single subcutaneous administration on the first day after operation. Overall survival days were compared. Continuous flat parallel concentration profiles were significant for 10 days from the first day after a single subcutaneous administration of TLBM (P <.01). The relationship between the dosages of TLBM administration and area under the concentration-time curve (AUC) up to 18 days demonstrated a linear regression line (P <.01). In addition, the relationship between the dose of TLBM and the survival days of the recipients in the liver transplantation model showed a positive correlation. The current pharmacokinetic study of TLBM revealed significantly increased tacrolimus levels in the regional lymph nodes compared with other organs except bone marrow (P <.01). In conclusion, TLBM allowed tacrolimus to release gradually in a very stable manner for 10 days, with dose-dependent immunosuppression after a single subcutaneous administration. The main site of TLBM uptake after subcutaneous administration was the regional lymph node of administration site.

Hepatic venous stenosis-related reduction of cyclosporin clearance in a pediatric patient after liver transplantation.

A 20-month-old girl with Alagille syndrome developed stenosis of hepatic venous anastomosis after living related-donor liver transplantation. Cyclosporin (a microemulsion formulation) was given orally at a dose of 50 mg twice daily, and the trough blood concentration was relatively stable. Before balloon angioplasty of the hepatic vein, trough cyclosporin blood concentrations became elevated and consequently, the dosage was reduced to 15 mg twice daily. On the day of angioplasty, the calculated elimination rate constant of cyclosporin was 0.036 hr(-1), while its apparent basal value was 0.078 hr(-1). The cyclosporin trough concentration to dosage (C/D) ratio gradually increased reaching the maximum on the day after angioplasty. Thereafter, the C/D ratio promptly decreased. Thus, it is speculated that the increase in cyclosporine C/D ratio was mainly dependent on reduction of hepatic clearance of cyclosporin due to hepatic congestion caused by the stenosis of the hepatic venous anastomosis.