Hiroko Wakasugi

Effect of clarithromycin on renal excretion of digoxin: Interaction with P‐glycoprotein

We present a digoxin‐clarithromycin interaction in two patients in whom digoxin concentrations were unexpectedly increased. The ratio of renal digoxin clearance to creatinine clearance in one patient was lower during the concomitant administration of clarithromycin (0.64 and 0.73) than that after cessation of clarithromycin administration (1.30 ± 0.20; mean ± SD). Because P‐glycoprotein could play an important role in the renal secretion of digoxin, we hypothesized that clarithromycin decreases renal digoxin excretion by inhibiting P‐glycoprotein‐mediated transport. Digoxin transport was evaluated with use of a kidney epithelial cell line, which expresses the human P‐glycoprotein on the apical membrane by transfection with MDR1 complementary deoxyribonucleic acid. Clarithromycin inhibited the transcellular transport of digoxin from the basolateral to the apical side in a concentration‐dependent manner and concomitantly increased the cellular accumulation of digoxin. These results suggest that clarithromycin may inhibit the P‐glycoprotein‐mediated tubular secretion of digoxin, and this interaction mechanism may contribute to an increase in the serum digoxin concentration.

Organic Anion Transporter oatp2-Mediated Interaction between Digoxin and Amiodarone in the Rat Liver

AbstractPurpose. The interaction between amiodarone and digoxin has been known to increase serum concentrations of digoxin in humans and rats. In this study, we assessed the molecular mechanism(s) of that drug interaction, focusing on digoxin transport mediated by P-glycoprotein (Pgp) and by rat liver organic anion transporter (oatp2). Methods. Digoxin transport by Pgp and oatp2 was assessed using Pgp-overexpressing transfectant LLC-GA5-COL150 monolayers and oatp2-expressing Xenopus oocytes, respectively. The digoxin uptake into the isolated rat hepatocytes was also examined. Results. Amiodarone (10 μM) inhibited slightly the transcellular transport of digoxin in LLC-GA5-COL150 monolayers, whereas itraconazole (10 μM), a potent Pgp inhibitor, markedly blocked the transport. The digoxin uptake by the isolated rat hepatocytes and by the oatp2-expressing Xenopus oocytes was decreased markedly in the presence of amiodarone but not in the presence of itraconazole. In addition, amiodarone inhibited the oatp2-mediated digoxin uptake in a competitive manner with an apparent inhibition constant value of 1.8 μM. Conclusion. These findings suggest that rat oatp2 rather than Pgp may be one of the interaction sites for digoxin and amiodarone in the liver.

Evaluation of pharmacokinetic interaction between cyclosporin A and probucol in rats

AbstractPurpose. The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. Methods. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun® capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral® capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. Results. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun® (corn oil) and Neoral® (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral® (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol. Conclusion. The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.

Major factors inhibiting spread of novel antipsychotic monotherapy for schizophrenia: prescription survey in the psychiatric outpatient unit of Kyoto University Hospital

matography. There was a correlation between the risperidone dose and the plasma risperidone concentration. Similarly, a correlation was observed between the risperidone dose and the plasma 9-OH-RIS concentration. Significant correlations were observed between the plasma 9-OH-RIS concentration and the total score of the Positive and Negative Syndrome Scale for Schizophrenia, positive symptom scale score and negative symptom scale score. From these results it was determined that the plasma 9-OH-RIS concentration increases with the dose of risperidone, and the clinical effect is dependent on the plasma 9-OH-RIS concentration up to a certain concentration (approximately 50 ng/ml). On the other hand, when the plasma 9-OH-RIS concentration increases beyond this point, a further study with a larger number of subjects will be required to clarify whether the clinical effect of risperidone reaches a plateau or continues.