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Muhammad Abdulrazik; The Decisive Value of Contralateral Eye Results in Comparative Ocular Pharmacokinetic Studies of a Drug Versus its Prodrug. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1299.
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© ARVO (1962-2015); The Authors (2016-present)
The extent of drug retention in the untreated contralateral eye is being traditionally considered in concluding the net bioavailability in the treated eye. This study aims at studying the decisive value of contralateral eye results in a case of comparative pharmacokinetic (PK) study of a drug versus its prodrug.
The studied drug was 3H radiolabeled dexamethasone (in 0.1 % preparations) as a base (MW=392, logP=1.77) or as a lipophilic prodrug (MW=630, logP=7.93). In two separate PK's, the drug or its prodrug were determined in aqueous humor and vitreous of both eyes, as well as in the systemic blood and cerebrospinal fluid (CSF), at 15, 30, 45, 60, 120, 180 and 360 minutes after one single topical application (50 µL) to the cul-de-sac of the treated albino rabbit eye. The area under curve of drug concentration against time (AUC.0-last) was calculated (min. x ng/gr) for each sampled site in both PK's. The relative bioavailability, of the drug with respect to the prodrug, for each of the sampled sites was calculated as follows: F.rel = AUC.drug / AUC.prodrug.
F.rel values were 5.599, 1.533, 1.737, 1.359, 0.931 and 1.017 for treated eye aqueous, treated eye vitreous, blood, CSF, contralateral eye aqueous and contralateral eye vitreous respectively.
In the present study the relative bioavailability of dexamethasone (drug/prodrug) have surprisingly showed bioequivalence, between the drug and the prodrug, in the aqueous humor and vitreous of the contralateral eye. This bioequivalence was contrary to the decisive F.rel in the treated eye aqueous humor and vitreous, which was in favor of the drug over the prodrug in both cases, and with no correlation to the F.rel in either the blood or the CSF, where in both cases the results were again in favor of the drug over the prodrug . This discrepancy could be related to the main site of prodrug cleavage. Yet, the present results challenges the possibility of a single or one principle mediating-compartment between both eyes, including the traditional (systemic blood circulation) and the alternative (CSF) mediating-compartment assumptions. Finally, the traditional way of concluding the net bioavailability in the treated eye with reference to the contralateral eye (net bioavailability = AUC.treated - AUC.contralateral) should be questioned in cases of comparisons between a drug and its prodrug.
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