WHAT IS KNOWN AND OBJECTIVEDrug-induced long QT syndrome (diLQTS) is a rare but serious adverse drug reaction. Drug-drug interaction (DDI) is one of the risk factors for the development of diLQTS. However, the combinations of drugs that increase the risk of diLQTS have not been extensively investigated. This study was performed to analyse the potential DDIs that elevate the incidence of diLQTS using a spontaneous reporting system.METHODSThe Japanese Adverse Drug Event Report database from April 2004 to January 2020 was used to assess adverse event reports. We calculated the reporting odds ratio and 95% confidence interval for signal detection.RESULTS AND DISCUSSIONSignals for concomitant use risk were detected in 31 drug combinations. Combinations of antipsychotics and antidepressants were the most common (olanzapine & fluvoxamine, olanzapine & trazodone, quetiapine & paroxetine, sulpiride & fluvoxamine, sulpiride & trazodone). Sixteen, 17 and 21 combinations were designated as requiring precaution for concomitant use in at least one of the package inserts in Japan, the United States and the United Kingdom, respectively, although no such precautions were described for the remaining combinations. On the contrary, a combination of bepridil & clarithromycin was categorized as "X (avoid combination)" and two combinations (chlorpromazine & haloperidol, amiodarone & metildigoxin) were classified as "D (modify regimen)" in the Lexicomp^® risk rating.WHAT IS NEW AND CONCLUSIONThis study identified 31 combinations of drugs that may elevate the risk of diLQTS. The use of these drug combinations should be monitored more carefully in future.

2021-06-01·Drug Metabolism and Pharmacokinetics4区 · 医学

Estimation of absolute oral bioavailability without performing an intravenous clinical study

4区 · 医学

Article

作者: Akiyoshi, Takeshi ; Ohtani, Hisakazu ; Iwata, Risa ; Imaoka, Ayuko

The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (R_u) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature. The fraction excreted unchanged into urine (f_e) was calculated for healthy subjects by dividing the R_u value by the total recovery rate. The contribution of renal excretion to total clearance from the systemic circulation (R_ren) was estimated by subjecting oral clearance and creatinine clearance to regression in subjects with normal and impaired renal function. BA was estimated as f_e/R_ren and compared with the observed BA (BA_obs). The predicted BA values for 9 drugs fell within ±20% of their BA_obs. The examined approach makes it possible to estimate BA values for drugs with mean renal excretion values in healthy subjects and oral clearance in subjects with various renal function, without intravenous pharmacokinetic data.

2019-06-01·Regenerative Therapy3区 · 工程技术

Inhibitory effects of class I antiarrhythmic agents on Na+ and Ca2+ currents of human iPS cell-derived cardiomyocytes

3区 · 工程技术

ArticleOA

作者: Kurata, Yasutaka ; Notsu, Tomomi ; Fukumura, Kenta ; Tsuneto, Motokazu ; Shirayoshi, Yasuaki ; Li, Peili ; Miake, Junichiro ; Higashi, Yuhei ; Yonemizu, Sayaka ; Ninomiya, Haruaki ; Masuda, Keiichiro ; Hisatome, Ichiro

INTRODUCTIONHuman induced pluripotent stem cells (hiPSCs) harboring cardiac myosin heavy chain 6 promoter can differentiate into functional cardiomyocytes called "iCell cardiomyocytes" under blasticidin treatment condition. While iCell cardiomyocytes are expected to be used for predicting cardiotoxicity of drugs, their responses to antiarrhythmic agents remain to be elucidated. We first examined electrophysiological properties of iCell cardiomyocytes and mRNA levels of ion channels and Ca handling proteins, and then evaluated effects of class I antiarrhythmic agents on their Na⁺ and Ca²⁺ currents.METHODSiCell cardiomyocytes were cultured for 8-14 days (38-44 days after inducing their differentiation), according to the manufacturer's protocol. We determined their action potentials (APs) and sarcolemmal ionic currents using whole-cell patch clamp techniques, and also mRNA levels of ion channels and Ca handling proteins by RT-PCR. Effects of three class I antiarrhythmic agents, pirmenol, pilsicainide and mexiletine, on Na⁺ channel current (I_Na) and L-type Ca²⁺ channel current (I_CaL) were evaluated by the whole-cell patch clamp.RESULTSiCell cardiomyocytes revealed sinoatrial node-type (18%), atrial-type (18%) and ventricular-type (64%) spontaneous APs. The maximum peak amplitudes of I_Na, I_CaL, and rapidly-activating delayed-rectifier K⁺ channel current were -62.7 ± 13.7, -8.1 ± 0.7, and 3.0 ± 1.0 pA/pF, respectively. The hyperpolarization-activated cation channel and inward-rectifier K⁺ channel currents were observed, whereas the T-type Ca²⁺ channel or slowly-activating delayed-rectifier K⁺ channel current was not detectable. mRNAs of Nav1.5, Cav1.2, Kir2.1, HCN4, KvLQT1, hERG and SERCA2 were detected, while that of HCN1, minK or MiRP was not. The class Ia antiarrhythmic agent pirmenol and class Ic agent pilsicainide blocked I_Na in a concentration-dependent manner with IC₅₀ of 0.87 ± 0.37 and 0.88 ± 0.16 μM, respectively; the class Ib agent mexiletine revealed weak I_Na block with a higher IC₅₀ of 30.0 ± 3.0 μM. Pirmenol, pilsicainide and mexiletine blocked I_CaL with IC₅₀ of 2.00 ± 0.39, 7.7 ± 2.5 and 5.0 ± 0.1 μM, respectively.CONCLUSIONSIn iCell cardiomyocytes, I_Na was blocked by the class Ia and Ic antiarrhythmic agents and I_CaL was blocked by all the class I agents within the ranges of clinical concentrations, suggesting their cardiotoxicity.

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