Info

Q Q1 _l_I_I_I_I_I_I_I_I_I_I_I_1_t_I_I_I_I_I_I_I_t,_> I I I > ' ■ > I

0 100 200 300 400 500 600

Time (min)

Q Q1 _l_I_I_I_I_I_I_I_I_I_I_I_1_t_I_I_I_I_I_I_I_t,_> I I I > ' ■ > I

0 100 200 300 400 500 600

Time (min)

Figure 6 Concentration-time profiles of plasma, anterior chamber, and vitreous fluorescein after systemic administration (10 mg/kg): (O) plasma concentrations; (A) aqueous concentration; (O) vitreous concentration. The line drawn represents the nonlinear least-squares regression fit of the model to the concentration-time data. (Ref. 52.)

B. Ocular Pharmacology and Pharmacodynamic Experimentation

A second study using the dual-probe approach—simultaneous sampling of aqueous and vitreous humor using microdialysis—was conducted (52) for the examination of cephalosporin ocular pharmacokinetics and the pharmacodynamics of inhibitory drugs on the intraocular disposition of cephalosporins. New Zealand albino rabbits (2-2.5 kg) were kept under anesthesia throughout the experiment. The concentric and linear micro-dialysis probes were implanted into the vitreous and aqueous chambers, respectively, as described above (51). Microdialysate samples were collected every 20 minutes over a period of 10 h. The animals were allowed to stabilize for 2 hours prior to initiation of each experiment. The ocular pharmacokinetics of cephalosporins were investigated following intravi-treal administration of 500 mg dose of cephalexin, cephazolin, and cepha-lothin, respectively. In vivo inhibition experiments were conducted by coadministration of one of two dipeptides, gly-pro or gly-sar, with a 50 mg dose of cephalexin or cefazolin. The dipeptides were administered by a bolus injection into the vitreous 30 minutes prior to administration of the drugs, as well as by continuous perfusion through the vitreous probes to maintain the study state dipeptide concentrations throughout the experiment. The intravitreal elimination half-lives of cephalexin, cefazolin, and cephalothin after intravitreal administration were found to be 185.38 ± 27 .25 min, 111.40 ± 17.17 min, and 146.68 ±47.52 min, respectively. Higher aqueous cephalexin concentrations were observed in comparison to cefazolin concentrations. With respect to the pharmacokinetic parameters of cephalexin in the presence of gly-pro, increased AUC (~3-fold), decreased clearance 3-fold), and increased terminal elimination half-life 3.5fold) was observed. The cephalexin intravitreal concentration time course with or without inhibitor is presented in Figure 7. For cefazolin, no change in the pharmacokinetic parameters was observed except for an ^fourfold increase in terminal elimination half-life in the presence of gly-pro. Gly-sar had no significant effect on the pharmacokinetics of either drug.

An important first step toward the ultimate endpoint, the assessment of the pharmacodynamics of beta-adrenergic antagonists, involved characterization of the disposition of the proposed endogenous marker for aqueous humor turnover, ascorbate, discussed in the previous section (53). The utility of this approach was examined initially in the pioneering work of Becker (57,70,71,72) for the pharmacodynamics of a systemically administered carbonic anhydrase inhibitor (CAI), acetazolamide. CAIs decrease IOP via reduction in aqueous humor production (73). Ascorbate concentra-

Figure 7 Vitreous concentration-time profile of cephalexin (50 mg) in the presence of inhibitors after intravitreal administration. (Ref. 51.)

tions in aqueous humor were observed to increase following acetazolamide administration (70). This observation provided the impetus for examining ascorbate as an endogenous substrate for the assessment of aqueous humor production inhibition.

Examination of the pharmacodynamics of aqueous humor production by beta-adrenergic antagonists was performed with a novel approach, microdialysis sampling of aqueous humor ascorbate. The time course for ascorbate in aqueous humor was used in order to determine the relative changes in aqueous humor flow as a result of beta-blocker pharmacodynamics. The volume dilution technique (31,32) involves assessment of the time course of an exogenously administered dye in aqueous humor following pharmacodynamic modulation of aqueous humor production (Fig. 8A), as described previously. Due to the intrusiveness of the procedure, studies of this nature are possible only in anesthetized animals. Rittenhouse et al. (54) selected an approach that would permit examination in a conscious animal model and would minimize the number of exogenous substrates required for this examination. By using an endogenous substrate, ascorbate, a less intrusive method for the examination of in vivo aqueous humor turnover, was developed (Fig. 8B).

Was this article helpful?

0 0

Post a comment