D

Figure 4 Ideal sampling times for determining the pharmacokinetics of topical ocular drugs. (Adapted from Ref. 8.)

fined as a proportionality constant relating concentration to amount. Volume of distribution at steady-state (Vss) most closely reflects the distribution capacity and, as such, is the most useful measure of Vd. Unlike whole body Vss, determining Vss in the eye is particularly difficult because the amount of drug in the eye at any time is not known following a single topical ocular administration. Two approaches have been developed to overcome this obstacle. The first method uses a well affixed over the cornea of an anesthetized rabbit so that drug solution is in constant contact with the cornea and not the surrounding sclera (48,49). Drug solution remains on the cornea for 90-160 minutes until concentration of drug in the aqueous humor reaches steady state. This so-called topical infusion study, with constant rate input, can yield absorption rate constant, ocular clearance, and Vss.

The second method for determining Vss and distribution involves intracameral injection, which delivers a bolus dose directly into the anterior chamber. Conrad and Robinson used this approach to determined the volume of distribution in albino rabbits (50). Inulin yielded an aqueous humor volume of 287 mL in close agreement with that previously determined by other methods. The apparent volume of distribution of pilocarpine was twofold larger than the assumed apparent volume of 250-300 mL, indicating distribution into surrounding tissues. Rittenhouse et al. examined the ocular uptake and disposition of topical ocular ^-adrenergic antagonists in individual dogs and rabbits (51). Radiolabeled (3H) propranolol was administered intracamerally and topically, and microdialysis was performed to monitor concentrations of radioactivity in the anterior chamber. Ocular bioavailability was 5.6% and 55% in anesthetized dog and rabbit, respectively. The value in rabbit was outside the 1-10% range typically observed with topical ocular instillation. The high bioavailability may be related to the use of anesthesia, which can cause a reduction in blinking and precorneal drainage. Table 6 presents ocular Vd values determined using either technique for various drugs.

Reliable estimates of Vss are useful for establishing multiple dose regimens; however, because of the somewhat specialized methods needed to determine Vss in the eye following topical ocular administration, it is not surprising that Vss has been estimated for only a few drugs. An obvious alternative for evaluating distribution is to simply measure directly the concentration of drug in ocular tissues. Researchers have taken this approach

Table 6 Ocular Volumes of Distribution (Vd) for Various Drugs

Drug

Vd (mL)

Method

Ref.

2-Benzothiazolesulfonamide

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