进口与国产普罗帕酮的人体生物利用度及代谢的对比研究

COMPARATIVE STUDY ON THE BIOAVAILABILITY AND METABOLISM OF RYTOMONORM AND DOMESTIC PROPAFENONE TABLETS IN CHINESE HEALTHY VOLUNTEERS

本研究对比观察Ｋｎｏｌｌ产普罗帕酮（ｒｙｔｏｍｏｎｏｒｍ）片（Ｒ）与国产普罗帕酮片（Ｄ）在８名中国男性健康志愿者体内的生物利用度及代谢变化。采用同体随机交叉法将志愿者分成口服Ａ与Ｂ及静脉组。每组４人。Ａ、Ｂ组分别单剂口服Ｒ与Ｄ１５０ｍｇ和３００ｍｇ。血清普罗帕酮（ＰＦ）及代谢物５－羟普罗帕酮（５－ＯＨＰ）与Ｎ－去丙基普罗帕酮（ＮＤＰＰ）用反相ＨＰＬＣ方法测定。结果表明Ｒ与Ｄ绝对生物利用度分别是４４．００±３１．７８％与３０．９２±２７．３６％（Ｐ＜０．０２），Ｒ／Ｄ的相对生物利用度是２３５±１９５％。Ａ、Ｂ组ＰＦ的ＡＵＣ及Ｃｍａｘ均是Ｒ大于Ｄ，相差有显著性。Ｒ与Ｄ制剂的血浓度与剂量均呈非线性关系。静脉组未测得代谢物。Ａ组５－ＯＨＰ的Ｃｍａｘ与ＡＵＣ接近或大于ＰＦ，Ｂ组为ＰＦ的５０％。ＮＤＰＰ只在Ｂ组测到，其Ｃｍａｘ为ＰＦ的５％。以上提示单剂口服给药Ｒ制剂的生物利用度大于Ｄ制剂。ＰＦ主要代谢成５－ＯＨＰ，５－ＯＨＰ的抗心律失常作用应予重视。

Comparative study on the bioavailability and metabolism of rytomonorm (R)and domestic propafenone(D)tablets wax performed in eight healthy volunteers. A randomized, single-blind,cross-over study was adopted .The eight volunteers were randomly divided into oral group A, B and i. v. group, each group consisted of four persons.Group A and B took single oral dose of 150 mg and 300 mg respectively (both R and D).The i. v.group received 35 mg dose of intravenous R The washout period between experiments in the same volunteer was two weeks. Serum concentration of propafenone (PF) 5-hydroxypropafenone (5-OHP)and N-depropylpropafenone (NDPP) were measured by HPLC method.The mean (±SD) absolute bioavailability values of R and D were 44.00 ±15. 86%, 30.92 ±13.68 % respectively(P<0. 02). The mean relative bioavailability of R/D was 235 ±195%. For AUC0-24 and Cmax of PF, R was significangly greater than D both A and B groups. The curve of serum concentration of PF with dose in R and D was nonlinear. The metabolites cannot be measured in i. v. group.The all eight healthy volunteers were extensive metabolizers. The mean Cmax and AUC0-24 ratios of 5-OHP/PPF for R vs D were 1.13±1.06 vs 3.11±2.55 (P>0.05) and 0.82±0.50 vs3.01±2.28 (P>0.05) in the group A,were 0. 40±0.23 vs 0.50±0.33 (P>0.05) and 0.33±0. 18 vs 0.52±0.24 (P>0.05) in the group B.The concentrations of NDPP were only measured in the group B and the mean Cmax ratios of NDPP/PPF for R and D were 0.05 ±0.03 and 0.06 ±0.01 (P>0. 05). Our data suggest that the bioavailabitily of Rytomonorn is higher than domestic propafenone and that propafenone is maintly metabolized to 5-hydroxypropafenone after single oral doses in Chinese,so antiarrhythmic activity of 5-OHP in extensive metabolizers should be considered.