Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
J Ocul Pharmacol Ther. 2011 Jun;27(3):251-9. doi: 10.1089/jop.2010.0178. Epub 2011 Apr 14.
To investigate the metabolism of a new antiglaucoma difluoroprostaglandin, tafluprost, in ocular tissues and evaluate the distribution of the parent drug and its metabolites in ocular and systemic tissues after a single ocular administration to cynomolgus monkeys (Macaca fascicularis).
A single dose of an ophthalmic solution containing 0.0005%, 0.005%, or 0.05% [(3)H]tafluprost was topically instilled (20 μL/eye) to male and/or female cynomolgus monkeys to study tissue distribution and metabolism. Blood, ocular/systemic tissues, or excreta were collected until 24 h after dosing. The radioactivity of each sample was measured by liquid scintillation counting, and metabolites were characterized by liquid chromatography-mass spectrometry. The major metabolites found in ocular tissues were intracameraly administered to monkeys to confirm their effect on intraocular pressure (IOP).
Soon after dosing, high concentrations of drug-related radioactivity were observed in the cornea and bulbar/palpebral conjunctiva, followed by the iris, sclera, choroid with retinal pigmented epithelium, and aqueous humor. The highest concentration of radioactivity concentrations occurred in the anterior and posterior ocular tissues within 2 h after dosing. The radioactivity measured in the plasma and ocular tissues was proportional to the dose administered. The major metabolites of tafluprost identified in the ocular tissues were tafluprost acid and 1,2-dinor- and 1,2,3,4-tetaranor-tafluprost acid. The estimated concentration of tafluprost acid in the aqueous humor and ciliary body was enough to stimulate prostanoid FP-receptors. After hydrolysis to the acid form, the primary metabolic pathway of tafluprost was via β-oxidation and, subsequently, oxidation. No metabolic reactions to the 15-carbon position were observed. Tafluprost acid was shown to significantly lower the IOP, whereas 1,2-dinor- and 1,2,3,4-tetaranor-tafluprost acid did not.
Topically administered [(3)H]tafluprost was well absorbed into the ocular and systemic tissues of the primary nonclinical species, monkey. The amount of the pharmacologically active form, that is, tafluprost acid, was high enough to occupy the target FP receptors at the site of action. The pharmacokinetic and metabolic properties of this difluorinated prostaglandin in primates are believed to result in clinical benefits of a long-term IOP-lowering effect.
研究一种新型抗青光眼双氟前列腺素滴眼剂他氟前列素在眼部组织中的代谢情况，并评估单次眼部给药后亲代药物及其代谢物在眼部和全身组织中的分布。
雄性和/或雌性食蟹猴单次眼部滴注（20 μL/眼） 0.0005%、0.005%或 0.05%[3H]他氟前列素眼用溶液，以研究组织分布和代谢情况。在给药后 24 小时内收集血液、眼部/全身组织或排泄物。通过液体闪烁计数测量每个样品的放射性，通过液相色谱-质谱联用鉴定代谢物。在眼部组织中发现的主要代谢物被腔内给药给猴子，以确认它们对眼内压（IOP）的影响。
给药后不久，在角膜和球周/睑结膜中观察到高浓度的药物相关放射性，随后是虹膜、巩膜、脉络膜伴视网膜色素上皮和房水。在给药后 2 小时内，前、后眼部组织中放射性浓度最高。测量的血浆和眼部组织中的放射性与给予的剂量成正比。在眼部组织中鉴定出的他氟前列素的主要代谢物为他氟前列素酸和 1,2-二降-和 1,2,3,4-四降他氟前列素酸。房水和睫状体中他氟前列素酸的估计浓度足以刺激前列腺素 FP 受体。在转化为酸形式后，他氟前列素的主要代谢途径是通过β-氧化，然后是氧化。未观察到对 15-碳位置的代谢反应。他氟前列素酸可显著降低 IOP，而 1,2-二降-和 1,2,3,4-四降他氟前列素酸则没有。
局部给予[3H]他氟前列素可被主要非临床物种猴的眼部和全身组织良好吸收。具有药理活性的形式，即他氟前列素酸的量足以占据作用部位的靶 FP 受体。这种双氟前列腺素在灵长类动物中的药代动力学和代谢特性被认为可带来长期降低 IOP 的临床益处。
