Ocular pharmacokinetics of a novel tetrahydroquinoline analog in rabbit: compartmental analysis and PK-PD evaluation.

The elimination kinetics of the pharmacologically active compound 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4) were characterized along with pharmacodynamic (PD) measurements. Four compartmental models based on ocular anatomy, physiology, and possible absorption and disposition pathways were proposed to model the pharmacokinetic (PK) data in WinNonlin and the best model was chosen based on statistical and goodness-of-fit criteria. A three-compartment physiologic-based PK model with a bidirectional transfer between cornea and aqueous humor and a unidirectional transfer between aqueous humor and iris-ciliary body best described the data. The ocular PD parameters, maximum effect attributed to drug (E(max)) and drug concentration which produces 50% of maximum effect (EC(50)), were estimated with change in intraocular pressure (ΔIOP) as the effect (PD response) in the effect compartment model (PK-PD link model) using aqueous humor concentration-time and ΔIOP-time profiles. The link model better described the effect compartment concentrations than a simple E(max) model that used iris-ciliary body concentration-time data, indicating that there is an apparent temporal displacement between aqueous humor concentration (plasma/central compartment equivalent) and pharmacological effect. A physiologically plausible value of 0.0159 min(-1) was obtained for the drug elimination rate constant (k(eo)) from the effect site to account for equilibration time in the biophase. Hysteresis was observed for the iris-ciliary body, aqueous humor drug concentrations, and effect data, further confirming the utility of the link model to describe the PD of MC4.

Ocular pharmacokinetics of a novel tetrahydroquinoline analog in rabbit: absorption, disposition, and non-compartmental analysis.

The pharmacologically active compound (33% reduction in rabbit intraocular pressure recovery rate assay) 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4), which showed ocular hypotensive action and had optimum physicochemical properties, was characterized for its ocular absorption and distribution properties to better understand its in vivo potency in comparison with an inactive compound, N-ethyl-1,4-benzoxazine (MC1). Tissue distribution to various ocular tissues was determined after absorption by both corneal and conjunctival-scleral routes, following administration by the "topical infusion" technique. The rank order of penetration for both the compounds was cornea > iris-ciliary body > aqueous humor > lens > conjunctiva-sclera. Overall, MC4 had significantly higher concentrations than MC1 in various ocular tissues, but particularly in the iris-ciliary body, which is the site of action (biophase). Ocular disposition studies of the active compound MC4 were then conducted to characterize its elimination kinetics, and the pharmacokinetic parameters were determined by non-compartmental and moment analysis using equations specific to "topical infusion" technique: first-order absorption rate constant, 4.1 × 10(-4) min(-1) ; elimination rate constant, 0.012 min(-1) ; mean residence time, 39.6 min; steady-state volume of distribution, 0.721 mL; and aqueous humor ocular clearance, 8.44 µL/min. The results were consistent with the conclusion that MC4 is well absorbed and distributed to the active site.

Ocular hypotensive action of a novel tetrahydroquinoline analog in rabbit: physicochemical evaluation.

Four new molecular entities, N-ethyl-1,4-benzoxazine (MC1), 1-ethyl-6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (MC2), (R,S)-1-ethyl-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (MC3), and 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline MC4, based on the primary pharmacophore 1-ethyl-1,2,3,4-tetrahydroquinoline, were synthesized and tested for their physicochemical properties and pharmacological activities. The ocular hypotensive action was measured as percent intraocular pressure (%IOP) reduction, following topical administration in rabbit IOP recovery rate assay in vivo. The results were 4.8%, 14%, 4.5%, and 33% reduction for MC1, MC2, MC3, and MC4, respectively, with MC4 being the only statistically significant potent compound. The physicochemical properties such as solubility, distribution coefficient, and pKa were then determined in order to explain their pharmacological activities or lack thereof. MC4, the active compound, showed the highest solubility in pH 7.4 buffer, and in conjunction with ionization and distribution coefficient values, is expected to easily penetrate through the lipophilic corneal epithelium in comparison with the other compounds. Although the in vivo potency of MC4 can be attributed at least in part to its optimum physicochemical properties, it is important to note that differences in the receptor binding/potency, pharmacokinetic properties, and transporter interaction can also play a role in explaining the biological activity.