THE ROLE OF GENETICALLY-DETERMINED POLYMORPHIC DRUG-METABOLISM IN THE BETA-BLOCKADE PRODUCED BY PROPAFENONE
THE ROLE OF GENETICALLY-DETERMINED POLYMORPHIC DRUG-METABOLISM IN THE BETA-BLOCKADE PRODUCED BY PROPAFENONE
复制标题
DOI：
10.1056/nejm199006213222502
复制
发表时间：
1990-06-21
影响因子：
158.5
通讯作者：
WOOSLEY, RL
中科院分区：
文献类型：
--
作者：
LEE, JT;KROEMER, HK;WOOSLEY, RL
普萘洛尔和钠通道阻断剂普罗帕酮具有相同的结构特征。尽管普罗帕酮的β-阻滞作用在体外很容易证明，但临床上显著的β-阻滞作用在体内并不一致。在这项研究中，我们测试了一个假设，即遗传决定的普罗帕酮生物转化为5-羟基代谢产物的变化解释了药物β-阻断作用的变化。我们评估β-受体阻滞剂的减少所产生的心动过速的异丙肾上腺素和平板运动在14名正常受试者在治疗期间与安慰剂和普罗帕酮150，225和300毫克，每8小时，各5天。9名受试者（具有广泛代谢者表型）将大部分普罗帕酮代谢为5-羟基普罗帕酮，5名受试者（具有不良代谢者表型）不产生这种代谢物。在较低剂量下，两组均存在β-阻滞，但在代谢不良的受试者中显著更大，其中5-羟基化缺陷与较高的血浆普罗帕酮水平相关。在最高剂量下，在两组中观察到相似程度的β-阻滞。普罗帕酮在体外对β 2受体的亲和力也高于其主要代谢产物。我们得出结论，普罗帕酮治疗过程中的β-阻滞程度反映了母体药物代谢的遗传决定的变化，这是β-阻滞所必需的，普罗帕酮的这种作用在普罗帕酮5-羟基化缺陷的患者中大大增强。
Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenone''s beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drug''s beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.