Andersson Tommy
Experimental Medicine, AstraZeneca LP, Wilmington, Delaware 19850-5437, USA.
Clin Pharmacokinet. 2004;43(5):279-85. doi: 10.2165/00003088-200443050-00001.
Chirality is one of the main features of biology, and many of the processes essential for life are stereospecific, meaning that one out of two or more isomers may work best in a particular physiological situation. Could this be used in drug development and result in any clinical relevance and true therapeutic advance? There are occasions when the development of one of the isomers might be expected to be advantageous: for example, only one of the isomers may be active, only one of the isomers may cause adverse effects, or one of the isomers may have more advantageous pharmacological properties. As an example of the last, the successful development of esomeprazole will be described. Before the introduction of esomeprazole, the proton pump inhibitor omeprazole was the standard treatment for gastric acid-related diseases, such as gastro-oesophageal reflux disease. A serious type of gastro-oesophageal reflux disease is erosive oesophagitis, an increasingly common condition that may lead to life-threatening complications. Doubling the standard dose of omeprazole from 20 to 40 mg did not improve healing rates (74% versus 75%), and thus a substantial proportion of patients remained unhealed with standard treatment. The (S)-isomer of omeprazole, esomeprazole, was shown to heal more patients than omeprazole as a result of unique metabolic properties that clearly differentiates esomeprazole from omeprazole, the racemate. At comparable doses, these properties lead to several clinical advantages: higher bioavailability in extensive metabolisers (the majority of patients), lower exposure in poor metabolisers, less interindividual variation and a steeper dose-response curve at steady state resulting in a more pronounced inhibition of gastric acid secretion. Esomeprazole has been studied clinically for a variety of acid-related conditions, showing that the compound is as well tolerated and more effective with regard to healing and symptom relief than the recommended treatment with omeprazole. Thus, from this example it is clear that the exploration and development of single-isomer drugs may bring significant advances in treatment options.
手性是生物学的主要特征之一，许多生命必需的过程具有立体特异性，这意味着在两种或更多种异构体中，可能有一种在特定生理情况下效果最佳。这能否用于药物开发并产生临床相关性和真正的治疗进展呢？在某些情况下，开发其中一种异构体可能会带来优势：例如，只有一种异构体具有活性，只有一种异构体可能引起不良反应，或者其中一种异构体可能具有更有利的药理特性。作为最后一种情况的例子，将描述埃索美拉唑的成功开发。在埃索美拉唑推出之前，质子泵抑制剂奥美拉唑是治疗胃酸相关疾病（如胃食管反流病）的标准疗法。一种严重的胃食管反流病是糜烂性食管炎，这是一种日益常见的疾病，可能导致危及生命的并发症。将奥美拉唑的标准剂量从20毫克加倍至40毫克并不能提高愈合率（分别为74%和75%），因此相当一部分患者采用标准治疗仍未愈合。奥美拉唑的（S）-异构体埃索美拉唑，由于其独特的代谢特性，与消旋体奥美拉唑明显不同，显示出比奥美拉唑能治愈更多患者。在可比剂量下，这些特性带来了几个临床优势：在广泛代谢者（大多数患者）中生物利用度更高，在代谢不良者中暴露量更低，个体间差异更小，稳态时剂量反应曲线更陡，从而对胃酸分泌的抑制作用更明显。埃索美拉唑已针对多种与酸相关的病症进行了临床研究，结果表明，与推荐的奥美拉唑治疗相比，该化合物在耐受性方面相当，在愈合和症状缓解方面更有效。因此，从这个例子可以清楚地看出，单异构体药物的探索和开发可能会在治疗选择方面带来重大进展。
