Serum tocainide enantiomer concentrations in human subjects.
Serum tocainide enantiomer concentrations in human subjects.
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人类受试者的血清托卡尼对映体浓度。
DOI：
10.1111/j.1365-2125.1984.tb05012.x
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发表时间：
1984
影响因子：
3.4
通讯作者：
Moyer,TP
中科院分区：
文献类型：
--
作者：
Sedman,AJ;Gal,J;Mastropaolo,W;Johnson,P;Maloney,JD;Moyer,TP
托卡奈德(2-氨基-2‘，6’-丙酰亚胺盐酸盐)是一种新的抗心律失常药物，常有效地治疗人类危及生命的心律失常(Zipes&Troup，1978；Sonnhag，1980)。托卡胺的化学结构包括一个不对称的中心，该药物在临床上以外消旋的形式使用。尽管托卡胺对映体的抗心律失常作用尚未在人身上进行研究，但在小鼠模型中，R-(-)对映体的抗心律失常作用是S-(+)对映体的三倍(Byrnes等人，1979年)，而在冠状动脉结扎的狗身上，这两种对映体之间的抗心律失常活性差异较小(Byrnes等人，1979年)。此外，最近还报道了托卡胺在小鼠和大鼠体内的立体选择性代谢和肾脏排泄(Gal等人，1982)。这些报告促使我们研究，托卡胺对映体药代动力学和药理学行为的差异是否会使对受试者测量的托卡胺血清总浓度的解释复杂化。梅奥诊所的7名受试者在3年的时间里采集了血清样本，这些受试者参加了一项盐酸托卡胺紧急给药的实验方案(Maloney等人，1980年)。所有受试者都有危及生命的室性心律失常，这些心律失常对常规治疗无效。血清中的托卡胺浓度由医生自行决定，托卡胺对映体的浓度由先前报道的气-液色谱程序的改进(Sedman&Gal，1983)确定(Gal等人，1982)。所有患者的治疗总托卡胺血药浓度均为4-12，ug/ml(21-63，umol/L)(Winkle等人，1978年；Woosley等人，1977年)(表1)，使用外消旋托卡胺15-50 mg·kg-‘day-’。在同一患者中，S-(+)托卡胺与R-(-)托卡胺的比例为1.3：1至4：1，对映体比例的对象内变异几乎与受试者之间的变异一样大。临床参数，如托卡奈德剂量、其他药物或充血性心力衰竭、肾功能衰竭或肝功能不全的程度，不能解释对映体的变异性，尽管研究的患者人数可能太少，无法详细说明这些差异。这项研究的结果表明，托卡奈德对映体比率在受试者内和受试者之间存在很大的变异性，并表明具有相同的治疗性总托卡胺血清浓度的患者的血清中每种对映体的量可能显著不同。例如，如果S-(+)：R-(-)托卡胺对映体的范围为1.3：1到4：1，则在任何总浓度下存在的R-(-)对映体的量可能变化达2.2倍。托卡胺总量与S-(+)：R-(-)比值无直接关系。
Tocainide (2-amino-2', 6'-propionoxylidide hydrochloride) is a new antiarrhythmic agent often effective in the treatment of life-threatening arrhythmias in man (Zipes & Troup, 1978; Sonnhag, 1980). The chemical structure of tocainide includes an asymmetric centre and the drug is used clinically in the racemic form. Al-though the antiarrhythmic properties of the tocainide enantiomers have not been studied in man, the R-(-) enantiomer is three times more potent than the S-(+) isomer as an antiarrhythmic agent in a mouse model (Byrnes et al., 1979) and smaller differences in antiarrhythmic activity between the enantiomers have been demon-strated in coronary-ligated dogs (Byrnes et al., 1979). In addition, stereoselective metabolism and renal excretion of tocainide in mice andrats also has been reported recently (Gal etal., 1982). These reports prompted us to examine if differences in tocainide enantiomer pharmacokinetic and pharmacologic behaviour could complicate interpretation of total tocainide serum concen-trations measured in human subjects. Serum sampleswere obtained over a 3-year period from seven subjects at theMayo Clinic, who were enrolled into an experimental protocol for the emergency administration of tocainide hydrochloride (Maloney et al., 1980). All sub-jects had life-threatening ventricular arrhythmias which were unresponsive to conventional therapy. Serum tocainide concentrations were obtained at physician discretion, and tocainide enantiomer concentrations determined by a modification (Sedman & Gal, 1983) ofa previously reported gas-liquid chromatographic procedure (Gal et al., 1982). Therapeutic total tocainide serum concentrations of 4-12, ug/ml (21-63, umol/l)(Winkle et al., 1978; Woosley et al., 1977) were obtained in all patients (Table 1), utilizing racemic tocainide doses of 15-50mg kg-'day-'. Ratios of S-(+) tocainide to R-(-) tocainide ranged from 1.3: 1 to 4: 1 in thesesame patients and intrasubject variability of enantiomer ratio was nearly as large as the variability between subjects. Clinical parameters such as tocainide dosage, other medications, or degree of congestive heart failure, renal failure or hepatic dysfunction, did not explain enantiomer variability, although the number of patients studied may be too small to elaborate such differences.The results of this study demonstrate a large intra-and intersubject variability of tocainide enantiomer ratios and suggests that patients with identical, therapeutic total tocainide serum con-centrations may have markedly different amounts of each enantiomer in their serum. For example, if the range of S-(+): R-(-) tocainide enantiomers of 1.3: 1 to 4: 1 is representative of that found in most patients, the amount of R-(-) enantiomer present at any total tocainide con-centration may vary by up to 2.2 fold. There was no direct relationship observed between the total amount of tocainide and the S-(+): R-(-) ratio.