Kasim Nehal A, Whitehouse Marc, Ramachandran Chandrasekharan, Bermejo Marival, Lennernäs Hans, Hussain Ajaz S, Junginger Hans E, Stavchansky Salomon A, Midha Kamal K, Shah Vinod P, Amidon Gordon L
College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Mol Pharm. 2004 Jan 12;1(1):85-96. doi: 10.1021/mp034006h.
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 < or = 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 (r2 = 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 Pwere 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.
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）基本药物清单中出现的速释剂型药物进行初步分类。本报告中的分类基于常见参考文献中报道的药物水溶性，以及一组29种参比药物的人体肠膜通透性与其计算的分配系数之间的相关性。WHO基本药物清单总共包括325种药品和260种药物，其中123种是速释（IR）产品中的口服药物。剂量数小于或等于1 [Do =（最大剂量强度/250 mL）/溶解度≤1]的药物被定义为高溶解度药物。使用《默克索引》或《美国药典》中报道的不带电荷、最低溶解度形式的药物溶解度。在WHO的123种速释剂型口服药物中，67%（82种）被确定为高溶解度药物。通透性分类基于29种参比药物的人体肠通透性与估计的log P或CLogP亲脂性值之间的相关性。选择美托洛尔作为通透性和log P或CLogP的参比化合物。104种药物的log P和CLogP呈线性相关（r2 = 0.78）。WHO清单上分别有53种（43.1%）和62种（50.4%）药物的log P和CLogP估计值大于或等于相应的美托洛尔值，被分类为高通透性药物。使用剂量数和log P将速释剂型药物分类为BCS 1类、2类、3类和4类药物的百分比分别为：1类23.6%，2类17.1%，3类31.7%，4类10.6%。其余17.1%的药物由于缺少片段无法计算log P值而无法分类。使用剂量数和CLogP标准在各BCS类别中的相应百分比相似：1类28.5%，2类19.5%，3类35.0%，4类9.8%。其余7.3%的药物由于无法计算CLogP而无法分类。这些结果表明，对于WHO基本药物清单上超过55%的高溶解度1类和3类药品，令人满意的生物等效性（BE）试验可能基于体外溶出试验。使用更易于实施、常规监测且可靠的体外溶出试验可以确保WHO基本药物清单上药品的临床性能。
