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kinetics of pilocarpine following topical application to the rabbit eye. From their work an equation was developed for tp:

ln(kna/ka)

Kna Ka

In Eq. (3), kna and ka are the nonabsorptive loss rate constant and the transcorneal absorption rate constant, respectively. Equation (3) assumes that kna is much larger than uptake into the epithelium of the cornea from the precorneal area. This assumption can be applied to most, if not all, ophthalmic drugs, since kna is approximately twofold larger than ka.

On occasion, a drug cannot be given systemically by a bolus intravenous dose, and therefore equations have been developed so that a slow intravenous infusion could be used instead (74,75). Eller et al. (76) developed a topical infusion technique for estimating the ophthalmic pharmacokinetics of drugs, which was based upon noncompartmental methods. The procedure consisted of maintaining a constant concentration of drug on the cornea through the use of a plastic cylinder secured over the sclera, which allowed only the cornea to be exposed to drug solution (see Table 3). A volume of 0.7 mL is maintained over the cornea of an anesthetized rabbit until steady-state ocular concentrations are reached. Rabbits are sacrificed at various time intervals, ocular tissues aer excised, and then assayed for drug content. This topical infusion approach permits an estimate of ka the apparent volume of distribution at steady state (Vss), and ocular clearance

Table 3 Topical Infusion Method Depicting Wella and Equations'3

Ocular well used for topical infusion Equations used for topical infusion method

k = VAdCJdtX

cwvw

K0T AUC

K0T AUMC K0T

a Well is a fixed over cornea of anesthetized rabbit; drug solution is maintained at a constant concentration for 90-160 minutes until steady-state concentrations of drug are reached in the aqueous humor.

b Ka = first-order transcorneal rate constant; Va = volume of the anterior chamber; (dCa/dt)I = initial rate of appearance of drug in aqueous humor minus lag time; C10 = ocular clearance (mL/min); K0 = constant rate of input into anterior chamber; AUC and AUMC = areas (to infinity) under the aqueous humor concentration x time curve and concentration x time-time curve, respectively; CW = constant concentration maintained on the cornea over time (90-160 min); VW = volume of drug solution maintained in well.

(Clo). Figure 4 shows a semilogarithmic plot of the aqueous humor concentration of ibufenac and ibuprofen following topical infusion of 0.3% maintained on the cornea for 120 minutes (51). Table 3 lists the equations and pharmacokinetic parameter values for drugs for which this procedure has been used.

2. Distribution

The volume of distribution represents a proportionality constant to relate concentration to amount or dose and also as a relative measure of tissue accumulation. It is the most difficult pharmacokinetic process to measure primarily because the amuont of drug in the eye at any time is not known. Aqueous humor is the circulating fluid of the eye, and in order to measure Vd accurately, an instantaneous input (i.e., intracameral injection) or an injection at a known rate must be introduced. Estimates of apparent volumes of distribution are lacking for ocular drugs. Table 4 lists values estimated either from an intracameral injection (see figure 5) or from topical

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