Adachi Koichiro, Beppu Satoru, Terashima Mariko, Kobari Wataru, Shimizu Makiko, Yamazaki Hiroshi
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan.
Kyoto Medical Center, Fushimi-ku, Kyoto, 612-8555, Japan.
J Pharm Health Care Sci. 2021 Aug 2;7(1):32. doi: 10.1186/s40780-021-00215-w.
Although the over-the-counter H receptor antagonist diphenhydramine is not a common drug of abuse, it was recently recognized as one of the substances causing acute poisoning in patients attempting suicide that led to admissions to our hospital emergency room.
Two patients [women aged 21 and 27 years (cases 1 and 2)] were emergently admitted after intentionally taking overdoses of 900 and 1200 mg diphenhydramine, respectively. The plasma diphenhydramine concentrations in case 1 were 977 and 425 ng/mL at 2.5 and 11.5 h after single oral overdose, and those in case 2 were 1320 and 475 ng/mL at 3 and 18 h after administration, respectively. We set up a simplified physiologically based pharmacokinetic (PBPK) model that was established using the reported pharmacokinetic data for a microdose of diphenhydramine. The two virtual plasma concentrations and the area under the curve (AUC) values extrapolated using the PBPK model were consistent with the observed overdose data. This finding implied linearity of pharmacokinetics over a wide dosage range for diphenhydramine.
The determined plasma concentrations of diphenhydramine of around 1000 ng/mL at ~ 3 h after orally administered overdoses in cases 1 and 2 may not have been high enough to cause hepatic impairment because levels of aspartate aminotransferase and alanine aminotransferase were normal; however, there was an increase in total bilirubin in case 1. Nonetheless, high virtual liver exposures of diphenhydramine were estimated by the current PBPK model. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide when setting the duration of treatment in cases of diphenhydramine overdose.
尽管非处方H受体拮抗剂苯海拉明并非常见的滥用药物，但最近它被认定为导致企图自杀的患者急性中毒并被收治入我院急诊室的物质之一。
两名患者（分别为21岁和27岁的女性，病例1和病例2）在故意过量服用900毫克和1200毫克苯海拉明后被紧急收治。病例1单次口服过量后2.5小时和11.5小时的血浆苯海拉明浓度分别为977纳克/毫升和425纳克/毫升，病例2给药后3小时和18小时的血浆苯海拉明浓度分别为1320纳克/毫升和475纳克/毫升。我们建立了一个简化的基于生理的药代动力学（PBPK）模型，该模型是利用报道的微量苯海拉明药代动力学数据建立的。使用PBPK模型推断的两个虚拟血浆浓度和曲线下面积（AUC）值与观察到的过量用药数据一致。这一发现表明苯海拉明在很宽的剂量范围内药代动力学呈线性。
病例1和病例2口服过量后约3小时测得的苯海拉明血浆浓度约为1000纳克/毫升，可能不足以导致肝功能损害，因为天冬氨酸转氨酶和丙氨酸转氨酶水平正常；然而，病例1的总胆红素有所升高。尽管如此，当前的PBPK模型估计苯海拉明在肝脏中的暴露量较高。基于药物监测数据和药代动力学预测的当前结果可为设定苯海拉明过量病例的治疗持续时间提供有用指导。
