Vitreous Disposition of Two Acycloguanosine Antivirals in the Albino and Pigmented Rabbit Models: A Novel Ocular Microdialysis Technique

Hughes, Patrick M.; Krishnamoorthy, Ramesh; Mitra, Ashim K.

doi:10.1089/jop.1996.12.209

Cited by 51 publications

(24 citation statements)

References 17 publications

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“…The amount administered should be in the first case 10-20% (representing probe recovery) of 12 mg and in the second 20-30% of 120 mg. This is considerably less than the 200 mg injected in the above mentioned experiment (Hughes et al 1996) and yet the calculated vitreous concentration obtained in our case is higher. This probably means that we are in fact measuring only the radioactivity of the vitreous surrounding the probe.…”

Section: Discussioncontrasting

confidence: 60%

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Ganciclovir delivery through an intravitreal microdialysis probe in rabbit

Waga

2000

Acta Ophthalmologica Scandinavica

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ABSTRACT.The treatment of cytomegalovirus retinitis has during the last years been done mainly with sustained release ganciclovir devices implanted in the vitreous. In the present study it is shown that ganciclovir can be administered into the rabbit vitreous by microdialysis. A concentration of about 10 ª6 M, which is considered within the therapeutic range, is achieved in the vitreous after a microdialysis perfusion. The method offers possibility of variation in the drug delivery that is not possible with the ganciclovir implants.

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Section: Discussioncontrasting

confidence: 60%

“…In the retrodialysis samples the same proportion is 1/10. Hughes et al (1996) state that an equilibrium is obtained within 4 h from the intravitreal injection of a bolus dose. Our administration lasts for 2 h, and probably the equilibrium takes longer.…”

Section: Discussionmentioning

confidence: 99%

Ganciclovir delivery through an intravitreal microdialysis probe in rabbit

Waga

2000

Acta Ophthalmologica Scandinavica

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“…The application of this technique in ocular drug kinetics has had a major impact on the study of drug disposition in the eye (Sato et al, 1996;Rittenhouse et al, 1999). It has been used in both the aqueous and vitreous chambers in several laboratories (Hughes et al, 1996;Waga and Ehinger, 1997). In our laboratory, we have successfully used this technique to study the disposition of drugs in the aqueous and vitreous chambers simultaneously (Macha and Mitra, 2001).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Erythromycin in Rabbit Corneas after Single-Dose Infusion: Role of P-Glycoprotein as a Barrier to in Vivo Ocular Drug Absorption

Dey

Gunda²,

Mitra³

2004

J Pharmacol Exp Ther

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Efflux pump like P-glycoprotein (P-gp) is known to be a major barrier to drug delivery. Functional P-glycoprotein has been recently identified in cornea and corneal cell lines. Thus, it is probable that P-glycoprotein may restrict in vivo ocular drug absorption, resulting in low ocular bioavailability. Experiments were designed using New Zealand albino (New Zealand White) rabbits to assess inhibitors of P-gp efflux to increase drug absorption. Anesthetized rabbits were given constant topical infusions of [14 C]erythromycin in the presence and absence of inhibitors. Testosterone, verapamil, quinidine, and cyclosporine A were selected as P-gp inhibitors. Transport experiments were conducted in Madin-Darby canine kidney cells transfected with the human mdr1 gene (MDCK-MDR1). Erythromycin exhibited significant efflux out of MDCK-MDR1 cells, suggesting that erythromycin is a good substrate for P-gp. Ocular pharmacokinetic studies were conducted using a topical single-dose infusion method. Maximum inhibition of P-gp mediated efflux was observed with 500 M testosterone. Area under the curve (AUC) 0-ϱ of erythromycin with 500 M testosterone was almost 4 times higher than AUC 0-ϱ without any inhibitor. Rate of elimination (k 10 ) for erythromycin and those with inhibitors was found to be similar (141 Ϯ 23 min), suggesting that elimination pathways were not altered. All the inhibitors were found to be nontoxic. Verapamil also inhibited the efflux pump with moderate change in AUC 0-ϱ and C max compared with control. Thus, P-gp is found to be active in vivo, and it restricts topical erythromycin absorption across the cornea, which can be inhibited by known P-gp inhibitors. Therefore, ocular bioavailability of P-gp substrates can be significantly enhanced by proper selection of P-gp inhibitors.

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“…The major constraint to the development and assessment of posterior segment pharmacokinetics of drugs in animal models is the inaccessibility of the ocular fluids for continuous serial sampling. Microdialysis has gained wide recognition as a standard technique for sampling various tissues and fluids such as brain, liver, kidney, skin, tumor, bile, and blood (Diaz et al, 1992;Robinson, 1995;Maggs et al, 1997), as well as anterior and vitreous chambers of the eye (Stemples et al, 1993;Hughes et al, 1996;Sato et al, 1996;Waga and Ehinger, 1997;Rittenhouse et al, 1999;Macha and Mitra, 2001a,b). We have developed an animal model in our laboratory for simultaneous and continuous sampling of the vitreous and aqueous humors in rabbits using microdialysis technique (Macha and Mitra, 2001a).…”

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confidence: 99%

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Macha¹,

Mitra²

2002

Drug Metab Dispos

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ABSTRACT:The present study was carried out to delineate the ocular pharmacokinetics of ganciclovir (GCV) following intravitreal administration. Another objective was to achieve sustained therapeutic concentrations of GCV in the vitreous over a prolonged period of time using its acyl monoester prodrugs (acetate, propionate, butyrate, and valerate). New Zealand albino male rabbits (2-2.5 kg) were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous using a 21-guage needle, and a linear microdialysis probe was implanted in the anterior chamber across the cornea using a 25-guage needle. The probes were perfused with isotonic phosphate buffer saline (pH 7.4) at a flow rate of 2 l/min. The drugs were administered (0.2 moles) intravitreally and the samples were collected every 20 min over a period of 10 h. The vitreal terminal elimination half-life (t 1/2 ␤) of GCV was found to be 426 ؎ 109 min. The hydrolysis rate and vitreal clearance of the prodrugs increased with the ascending ester chain length. The vitreal elimination half-lives (t 1/2k10 ) of GCV, acetate, propionate, butyrate, and valerate esters of GCV were 170 ؎ 37, 117 ؎ 50, 122 ؎ 13, 55 ؎ 26, and 107 ؎ 14 min, respectively. A parabolic relationship was observed between the vitreal elimination rate constant and the ester chain length. Mean residence time (MRT) of the regenerated GCV following prodrug administration was found to be three to four times the value obtained after GCV injection. In conclusion, these studies have shown that the ester prodrugs generated therapeutic concentrations of GCV in vivo, and the MRT of GCV could be enhanced by 3-to 4-fold through prodrug modification.

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Vitreous Disposition of Two Acycloguanosine Antivirals in the Albino and Pigmented Rabbit Models: A Novel Ocular Microdialysis Technique

Cited by 51 publications

References 17 publications

Ganciclovir delivery through an intravitreal microdialysis probe in rabbit

Ganciclovir delivery through an intravitreal microdialysis probe in rabbit

Pharmacokinetics of Erythromycin in Rabbit Corneas after Single-Dose Infusion: Role of P-Glycoprotein as a Barrier to in Vivo Ocular Drug Absorption

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

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