S Macha

Publications (2)4.77 Total impact

• Article: Ocular pharmacokinetics of cephalosporins using microdialysis.

  S Macha, A K Mitra
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  ABSTRACT: The purpose of this study was to delineate the ocular pharmacokinetics of cephalosporins and investigate the presence of peptide transporters in the retina. New Zealand albino rabbits were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous chamber and linear probe across the cornea in the aqueous humor. Isotonic phosphate buffer saline was perfused through the probes, and samples were collected every 20 min over a period of 10 hr. A 500 microg dose of cephalexin, cephazolin, and cephalothin was administered intravitreally. Inhibition experiments were carried out in vivo, using gly-pro and gly-sar. The vitreal half-lives of cephalexin, cefazolin, and cephalothin were 185.38 +/- 27.25 min, 111.40 +/- 17.17 min, and 146.68 +/- 47.52 min, respectively. Cephalexin generated higher aqueous humor concentrations compared to cefazolin. The pharmacokinetic parameters of cephalexin in the presence of gly-pro, i.e., AUC (44452.06 +/- 3326.55 microg x min/ml), clearance (0.0013 +/- 0.0004 ml/min) and vitreal half-life (825.12 +/- 499.95 min) were different from that of the control (14612.83 +/- 4036.47 microg x min/ml, 0.0036 +/- 0.0011 ml/min, and 187.96 +/- 65.12 min, respectively). Gly-pro did not inhibit cefazolin, and gly-sar showed no effect on the pharmacokinetics of both drugs. These studies indicate the involvement of a peptide carrier in the transport of cephalosporins across the retina. Although gly-pro inhibited the elimination of cephalexin from the vitreous, the effect of an alpha-amino group on peptide carriers was not clearly evident.
  Journal of Ocular Pharmacology and Therapeutics 11/2001; 17(5):485-98. · 1.51 Impact Factor
• Article: Ocular pharmacokinetics in rabbits using a novel dual probe microdialysis technique.

  S Macha, A K Mitra
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  ABSTRACT: Ocular infections involve delicate internal structures of the eye that often require treatment with antimicrobial agents. A major constraint to the study of ocular drug absorption from systemic administration is the inaccessibility of the vitreous for continuous serial sampling. A novel dual probe microdialysis technique has been employed in our laboratory, which will enable the delineation of complete ocular pharmacokinetics of a drug. New Zealand albino rabbits weighing 2--2.5 kg were used. The animals were kept under anesthesia throughout the experiment. A concentric probe was implanted in the vitreous chamber about 3 mm below the corneal scleral limbus. Simultaneously a linear probe was implanted in the anterior chamber across the cornea. Intraocular pressure (IOP) was measured using Schiotz tonometer. The total protein concentrations in the aqueous and vitreous humors were determined using the Bio-Rad protein assay method. The aqueous and vitreous elimination kinetics of fluorescein were studied after intravitreal and systemic administrations over a period of 10 hr. Microdialysis technique was also compared to the conventional direct sampling technique by determining the intravitreal kinetics of fluorescein. Results suggest that IOP reverted to normal within 2 hr after the implantation of the probes. The increase in the vitreal total protein concentration was not significantly different from the baseline. The increase in the aqueous total protein concentration was less than five times the basal concentration throughout the experiment. The blood-aqueous and blood-retinal barrier integrity was delineated by determining the permeability index for fluorescein and were found to be 9.48 +/- 4.25% and 1.99 +/- 0.66% for the anterior and vitreous chamber, respectively. The rate constant of penetration of fluorescein into the anterior chamber was found to be 8.48 +/- 1.33 x 10(-2) min(-1), which was significantly higher than into the vitreous i.e. 4.34 +/- 2.82 x 10(-2) min(-1). The terminal elimination rate constant of fluorescein from the anterior chamber (1.48 +/- 0.79 x 10(-2) min(-1)) was found to be similar to that of the plasma terminal elimination rate constant (1.57 +/- 0.25 x 10(-2) min(-1)), but significantly higher than from the vitreous (3.0 +/- 0.7 x 10(-3) min(-1)). The terminal vitreal elimination rate constant of fluorescein after intravitreal administration was found to be similar by both microdialysis (3.98 +/- 0.6 x 10(-3) min(-1)) and direct sampling (4.38 +/- 1.4 x 10(-3) min(-1)) techniques. In case of direct sampling technique the area under the vitreous concentration-time curve was higher compared to that obtained by the microdialysis technique. There was no breakdown of the blood ocular barriers as shown by a very small change in the intraocular fluid protein concentrations. This was also confirmed by the fluorescein kinetics, which were in accordance with the previous studies. IOP data suggests that the intraocular fluid dynamics were not affected and the animals stabilized within 2 hr after the implantation of the probes. Fluorescein data suggests that the vitreous compartment is surrounded by a tighter barrier compared to the anterior chamber. This technique appears to be more sensitive, reproducible and requires only one animal for the determination of entire ocular pharmacokinetic profile.
  Experimental Eye Research 04/2001; 72(3):289-99. · 3.26 Impact Factor