Molecular properties of WHO essential drugs and provisional biopharmaceutical classification
Molecular properties of WHO essential drugs and provisional biopharmaceutical classification
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DOI：
10.1021/mp034006h
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发表时间：
2004-01-12
影响因子：
4.9
通讯作者：
Amidon, Gordon L.
中科院分区：
文献类型：
--
作者：
Kasim, Nehal A.;Whitehouse, Marc;Amidon, Gordon L.
本研究的目的是根据生物药剂学分类系统（BCS）对世界卫生组织（WHO）基本药物清单上的速释剂型药物进行临时分类。本报告中的分类基于常用参考文献中报告的药物的水溶性以及一组29种参比药物的人体肠膜渗透性与其计算分配系数的相关性。世卫组织基本药物清单共包括325种药物和260种药物，其中123种为速释产品中的口服药物。剂量数小于或等于1的药物[Do =（最大剂量规格/250 mL）/溶解度：5 1]定义为高溶解度药物。使用Merck Index或USP中报道的不带电荷的最低溶解度形式的药物溶解度。在123种世卫组织口服速释剂型药物中，67%（82种）被确定为高溶解度药物。渗透性的分类是基于29种参比药物的人体肠道渗透性与估计的log P或CLogP亲脂性值的相关性。选择美托洛尔作为渗透性和log P或CLogP的参比化合物。104种药物的LogP与CLogP呈线性相关（r（2）= 0.78）。WHO列表中共有53种（43.1%）和62种（50.4%）药物分别显示log P和CLogP估计值大于或等于相应的美托洛尔值，并被归类为高渗透性药物。使用剂量编号和log P分类为BCS 1类、2类、3类和4类药物的速释剂型药物百分比如下：1类23.6%，2类17.1%，3类31.7%，4类10.6%。其余17.1%的药物无法分类，因为缺失片段导致无法计算log P值。不同BCS类别中剂量编号和CLogP标准的相应百分比相似：1类28.5%，2类19.5%，3类35.0%，4类9.8%。其余7.3%的药物无法分类，因为无法计算CLogP。这些结果表明，WHO基本药物清单上超过55%的高溶解度1类和3类制剂的生物等效性（BE）试验可基于体外溶出试验。使用更容易实施、常规监测和可靠的体外溶出试验可确保世卫组织基本药物清单上所列药品的临床性能。
The purpose of this study is to provisionally classify, based on the Biopharmaceutics Classification System (BCS), drugs in immediate-release dosage forms that appear on the World Health Organization (WHO) Essential Drug List. The classification in this report is based on the aqueous solubility of the drugs reported in commonly available reference literature and a correlation of human intestinal membrane permeability for a set of 29 reference drugs with their calculated partition coefficients. The WHO Essential Drug List consists of a total of 325 medicines and 260 drugs, of which 123 are oral drugs in immediate-release (IR) products. Drugs with dose numbers less than or equal to unity [Do = (maximum dose strength/250 mL)/solubility :5 1] are defined as high-solubility drugs. Drug solubility for the uncharged, lowest-solubility form reported in the Merck Index or USP was used. Of the 123 WHO oral drugs in immediate-release dosage forms, 67% (82) were determined to be high-solubility drugs. The classification of permeability is based on correlations of human intestinal permeability of 29 reference drugs with the estimated log P or CLogP lipophilicity values. Metoprolol was chosen as the reference compound for permeability and log P or CLogP. Log P and CLogP were linearly correlated (r(2) = 0.78) for 104 drugs. A total of 53 (43.1%) and 62 (50.4%) drugs on the WHO list exhibited log P and CLogP estimates, respectively, that were greater than or equal to the corresponding metoprolol value and are classified as high-permeability drugs. The percentages of the drugs in immediate-release dosage forms that were classified as BCS Class 1, Class 2, Class 3, and Class 4 drugs using dose number and log P were as follows: 23.6% in Class 1, 17.1% in Class 2, 31.7% in Class 3, and 10.6% in Class 4. The remaining 17.1% of the drugs could not be classified because of the inability to calculate log P values because of missing fragments. The corresponding percentages in the various BCS classes with dose number and CLogP criteria were similar: 28.5% in Class 1, 19.5% in Class 2, 35.0% in Class 3, and 9.8% in Class 4. The remaining 7.3% of the drugs could not be classified since CLogP could not be calculated. These results suggest that a satisfactory bioequivalence (BE) test for more than 55% of the high-solubility Class 1 and Class 3 drug products on the WHO Essential Drug List may be based on an in vitro dissolution test. The use of more easily implemented, routinely monitored, and reliable in vitro dissolution tests can ensure the clinical performance of drug products that appear on the WHO Essential Medicines List.