Yorinobu Maeda

Dosage adjustment of ribavirin based on renal function in Japanese patients with chronic hepatitis C.

The daily dose of ribavirin is currently determined based on body weight. In the present study, the authors examined factors influencing total plasma clearance (CLtotal) and the toxic level on red blood cells of ribavirin in such body weight–based dosage adjustment in Japanese chronic hepatitis C patients (13 male and 6 female). Patients received ribavirin (600 or 800 mg/d) orally, depending on their body weights, together with interferon &agr;-2b (6 million units) intramuscularly. A steady-state trough plasma concentration (Cpss) was achieved approximately 4 weeks after the initiation of treatment, but the value was scattered among patients in a range from 1100 to 4200 ng/mL. The high Cpss of ribavirin of approximately 4000 ng/mL decreased hemoglobin concentrations to less than 8.5 g/dL. The individual CLtotal, estimated by dividing dose normalized by body weight by Cpss, of ribavirin correlated significantly with the patients creatinine clearance. In contrast, no relationship was observed with other parameters such as age, body weight, serum creatinine concentration, alanine aminotransferase (ALT) concentration, or aspartate aminotransferase (AST) concentration, though ALT and AST concentrations decreased with ribavirin treatment in most patients. These results indicate that CLtotal of ribavirin is dependent on renal function (creatinine clearance), and hemolysis is induced by high ribavirin concentrations in plasma. Dosage adjustment of ribavirin based on renal function and body weight would provide effective and safer treatment without causing hemolysis.

Possible mechanism for pharmacokinetic interaction between lidocaine and mexiletine

Our objective was to elicidate the mechanism of pharmacokinetic interaction between lidocaine and mexiletine, because an unexpected increase in plasma lidocaine concentration accompanied by severe side effects was observed when mexiletine was administered to a patient with dilated cardiomyopathy.

Dosage Adjustment of Dabigatran Etexilate Based on Creatinine Clearance in Patients With Cardioembolic Stroke or Atrial Fibrillation.

Background: A recommendation for dosage adjustment of dabigatran etexilate, a prodrug of dabigatran, seems to be desirable based on creatinine clearance to avoid bleeding and stroke. Methods: Outpatients and inpatients having a history of cardioembolic stroke or atrial fibrillation were included. After taking dabigatran etexilate orally (75–150 mg twice daily) for at least 1 week, plasma trough concentration (Ctrough, ng/mL) of dabigatran and creatinine clearance (CLcr, mL/min) of patients according to Cockcroft and Gault equation were determined. Results: Among the 38 patients studied, Ctrough of dabigatran and CLcr were scattered in a range from 31.4 to 329.5 ng/mL and 15.4–133.4 mL/min, respectively. Temporal CLtotal (Temp-CLtotal) of dabigatran, estimated by dividing the daily absorbed amount of dabigatran etexilate with Ctrough of dabigatran, was linearly correlated with CLcr of patients (P = 0.0018). Based on the findings, the daily dose of dabigatran etexilate that provides Ctrough of dabigatran at approximately 70 ng/mL was estimated. Conclusions: A linear relationship was found between Temp-CLtotal of dabigatran and CLcr of patients. Depending on CLxr of patients, we recommend 4 different dosages of dabigatran etexilate to obtain Ctrough of dabigatran at approximately 70 ng/mL.

Usefulness of one-point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1 genetic information after irinotecan administration

BackgroundIt was recently reported that genetic polymorphisms of UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1), a glucuronidation enzyme, were associated with irinotecan (CPT-11) metabolism. The active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38) was glucuronidated (SN-38G) by UGT1A1. Genetic polymorphisms of UGT1A1 were associated with potentially serious adverse events, including neutropenia. Several studies have suggested that the dose of CPT-11 should be decreased in patients homozygous for UGT1A1*6 or UGT1A1*28, or double heterozygotes (*6/*28). However, the reference dose for patients with these genetic polymorphisms is unclear.MethodsWe investigated the relationship between the SN-38G/SN-38 concentration ratio and the dose of CPT-11 in 70 patients with colorectal cancer who received FOLFIRI-based regimens, by measuring the plasma concentrations of CPT-11, SN-38, and SN-38G.ResultsThe SN-38G/SN-38 concentration ratio was lower in patients who were homozygous for UGT1A1*6, heterozygous for UGT1A1*6 or UGT1A1*28, or were double heterozygotes compared with patients with wild-type genes. The relative decreases in the SN-38G/SN-38 concentration ratio in patients homozygous for UGT1A1*6 and in double heterozygotes were greater than in patients heterozygous for UGT1A1*6 or UGT1A1*28. Interestingly, decreases in the SN-38G/SN-38 concentration ratio were associated with decreases in the neutrophil count and the final infusion dose of CPT-11.ConclusionOur results suggest that the SN-38G/SN-38 concentration ratio is an important factor for guiding dose adjustments, even in patients with wild-type genes. Therefore, the SN-38G/SN-38 concentration ratio, as an index of the patient’s metabolic capacity, is useful for assessing dose adjustments of CPT-11.

The Effect of Cimetidine on Renal Excretion of Chlorpropamide in Rabbits. (I).

Effects of co-administration of cimetidine (CMT) on pharmacokinetic behaviors of chlorpropamide (CPA), an oral hypoglycemic agent, after intravenous injection, were investigated in rabbits.The co-administration of CMT enhanced the plasma concentration of CPA, and reduced the amount of cumulative urinary excretion of CPA after intravenous bolus injection.Furthermore, the co-administration of CMT was found to decrease the renal clearance of CPA significantly, but to have no effect on its extrarenal clearance.These clearly indicate that the interaction of CPA with CMT is generated during renal excretion.For the purpose of elucidating the cause, effects of CMT on plasma protein binding of CPA, glomerular filtration rate (GFR), renal tubular secretion of PSP, and urinary pH were investigated.Plasma protein binding of CPA, GFR, and urinary pH were unchanged with and without CMT.But urinary excretion of PSP was decreased by co-administration of CMT.These observations suggest that the co-administration of CMT may depress the renal excretion of CPA by inhibiting the tubular secretion.