Rittenhouse K D, Peiffer R L, Pollack G M
Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
J Pharm Biomed Anal. 1998 Feb;16(6):951-9. doi: 10.1016/s0731-7085(97)00060-5.
The dynamics of beta-adrenergic-associated reductions in aqueous humor production for treatment of elevated intraocular pressure are not well understood. In particular, the relationship between ocular pharmacokinetics and pharmacodynamics has yet to be established. This study was undertaken to develop a procedure for examining the ocular absorption and disposition of topically administered ophthalmic beta-adrenergic antagonists in individual animals. Dogs were anesthetized with isoflurane and a microdialysis probe was implanted in the anterior chamber of one eye and perfused with 0.9% saline at a rate of 2 microliters min-1. 3H-propranolol was administered by intracameral injection or topically. Each dog received intracameral and topical propranolol, in alternate eyes on separate days, in a randomized cross-over fashion. Microdialysis probe effluent was collected every 5 min for > or = 2.5 h; concentrations of propranolol were determined by liquid scintillation spectroscopy and were corrected for probe recovery of the substrate as determined by in vivo retrodialysis (approximately 46%) to estimate aqueous humor concentrations. In separate experiments in rabbits, microdialysis probes were implanted in each eye. 3H-propranolol was administered topically to one eye; the contralateral eye received intracameral 3H-propranolol. Model-independent pharmacokinetic parameters for each treatment phase were calculated. The mean +/- S.D. times to peak concentration of propranolol in aqueous humor were 86.6 +/- 47.6 min in the dog and 54.1 +/- 20.4 min in the rabbit. The terminal rate constant was 0.0189 +/- 0.00429 min-1 in the dog vs. 0.00983 +/- 0.00546 min-1 in the rabbit. Intraocular tissue availability of propranolol differed markedly between the dog (n = 3) and rabbit (n = 3) (approximately 0.056 in the dog vs. approximately 0.55 in the rabbit). These results demonstrate the utility of microdialysis sampling for examination of ocular pharmacokinetics.
β-肾上腺素能相关的房水生成减少在治疗眼压升高方面的动力学尚未得到充分理解。特别是，眼药代动力学与药效学之间的关系尚未确立。本研究旨在开发一种程序，用于检查局部给药的眼科β-肾上腺素能拮抗剂在个体动物中的眼部吸收和处置情况。用异氟烷麻醉犬，将微透析探头植入一只眼睛的前房，以2微升/分钟的速率用0.9%生理盐水灌注。通过前房内注射或局部给药给予3H-普萘洛尔。每只犬以随机交叉方式在不同的日子里，在交替的眼睛中接受前房内和局部普萘洛尔给药。每5分钟收集微透析探头流出液≥2.5小时；通过液体闪烁光谱法测定普萘洛尔的浓度，并根据体内逆向透析确定的底物探头回收率（约46%）进行校正，以估计房水浓度。在兔的单独实验中，将微透析探头植入每只眼睛。对一只眼睛局部给予3H-普萘洛尔；对侧眼睛接受前房内3H-普萘洛尔给药。计算每个治疗阶段的非模型依赖药代动力学参数。犬房水中普萘洛尔达到峰值浓度的平均±标准差时间为86.6±47.6分钟，兔为54.1±20.4分钟。犬的终末速率常数为0.0189±0.00429分钟-1，兔为0.00983±0.00546分钟-1。犬（n = 3）和兔（n = 3）之间普萘洛尔的眼内组织可用性有显著差异（犬约为0.056，兔约为0.55）。这些结果证明了微透析采样在检查眼药代动力学方面的实用性。
