Pagliara A, Testa B, Carrupt P A, Jolliet P, Morin C, Morin D, Urien S, Tillement J P, Rihoux J P
Institut de Chimie Thérapeutique, Université de Lausanne, Switzerland.
J Med Chem. 1998 Mar 12;41(6):853-63. doi: 10.1021/jm9704311.
The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.
对组胺拮抗剂（H1受体拮抗剂）西替利嗪的离子化及亲脂性特征进行了研究，结果显示该药物在pH值为3.5 - 7.5的范围内几乎完全以两性离子形式存在。在此pH范围内，与阳离子型组胺拮抗剂相比，其正辛醇/水分配系数恒定且较低（log D = log PZ = 1.5），而其氢键结合能力相对较强（δlog PZ≥3.1）。构象、电子及亲脂性势能计算结果表明，两性离子形式的西替利嗪在低极性的折叠构象中会发生部分分子内电荷中和。药代动力学研究表明，该药物与血液蛋白高度结合，主要是血清白蛋白，且脑摄取率较低，这解释了其无镇静作用的原因。因此，西替利嗪与“第二代”组胺拮抗剂并无差异。相比之下，其在人体中的表观分布容积极低（0.4 L·kg-1，小于可交换水的表观分布容积），这意味着它对心肌等瘦组织的亲和力较低，且与该药物无心脏毒性相符。西替利嗪的两性离子性质及适度的亲脂性可能是导致这种药代动力学行为的原因。有人提出，西替利嗪及类似的两性离子，其物理化学、药代动力学及药效学性质与该类“第一代”和“第二代”药物不同，可被视为“第三代”组胺拮抗剂。
