Lee Y H, Kompella U B, Lee V H
Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
Exp Eye Res. 1993 Sep;57(3):341-9. doi: 10.1006/exer.1993.1133.
The objective of this study was to determine the influence of drug lipophilicity on extent of systemic absorption and relative contributions of the nasal and conjunctival mucosae to systemic absorption following topical solution instillation in the pigmented rabbit. Relatively hydrophilic atenolol, moderately lipophilic timolol and levobunolol, and lipophilic betaxolol were chosen as model drugs. Twenty-five microliters of a 15 mM drug solution in isotonic pH 7.4 buffer was instilled in each eye, with or without nasolacrimal occlusion, and plasma drug concentration was monitored using reversed phase HPLC. An equivalent amount of all four beta adrenergic antagonists was instilled directly into the nasolacrimal duct to assess the nasal contribution to systemic drug absorption following topical solution instillation. The systemic bioavailability ranged from 61% for atenolol to 100% for timolol. At least 50% of the systemically absorbed drug reached the bloodstream from the nasal mucosa; the nasal contribution was 83% for atenolol and 55-74% for the other three drugs. Occluding the nasolacrimal duct for 5 min reduced the extent of systemic absorption of timolol and levobunolol but did not do so for atenolol and betaxolol. Additional prolongation of solution retention in the conjunctival sac brought about further reduction for only atenolol (480-min prolongation) and timolol (120-min prolongation). Taken together, the above findings suggest that the systemic bioavailability of topically applied ophthalmic drugs would be modest for drugs at the extremes of lipophilicity and that the contribution of the nasal pathway to systemically absorbed drug diminishes with increasing drug lipophilicity.
本研究的目的是确定药物亲脂性对全身吸收程度的影响，以及在有色家兔局部滴入溶液后，鼻腔和结膜粘膜对全身吸收的相对贡献。选择相对亲水性的阿替洛尔、中度亲脂性的噻吗洛尔和左布诺洛尔以及亲脂性的倍他洛尔作为模型药物。在每只眼中滴入25微升等渗pH 7.4缓冲液中的15 mM药物溶液，有无鼻泪管阻塞，并用反相高效液相色谱法监测血浆药物浓度。将等量的所有四种β肾上腺素能拮抗剂直接滴入鼻泪管，以评估局部滴入溶液后鼻腔对全身药物吸收的贡献。全身生物利用度范围从阿替洛尔的61%到噻吗洛尔的100%。至少50%的全身吸收药物从鼻粘膜进入血液；阿替洛尔的鼻腔贡献为83%，其他三种药物为55 - 74%。阻塞鼻泪管5分钟可降低噻吗洛尔和左布诺洛尔的全身吸收程度，但对阿替洛尔和倍他洛尔则无此作用。结膜囊中溶液保留时间的进一步延长仅使阿替洛尔（延长480分钟）和噻吗洛尔（延长120分钟）的全身吸收进一步降低。综上所述，上述发现表明，对于亲脂性处于极端情况的药物，局部应用眼科药物的全身生物利用度适中，并且随着药物亲脂性的增加，鼻腔途径对全身吸收药物的贡献会降低。
