## Fd

In Eq. (1), D is the instilled dose (25 mL), k10 is the loss of drug from the precorneal area (1 x 10~2 min-1), and V is estimated as 0.3 mL. Extrapolating the results to normal rabbits, assuming a volume of distribution approximately equal to the aqueous humor volume, and assuming that negligible drug distributes out of the aqueous humor were approximations required in order to estimate F.

Since drug absorption across the cornea and loss of drug from the precorneal area are parallel loss processes, it was possible to confirm the results of Patton and Robinson (46) by the use of Eq. (2):

The fraction absorbed for a 25 mL instilled dose of pilocarpine nitrate in the rabbit eye was estimated to be 1-2% (46,47). Using Eq. (2), Chiang and Schoenwald calculated that for a 30 mL dose of 0.4% clonidine, an F of 1.6% was calculated for the rabbit eye (28).

Ling and Combs (73) compared the areas under the concentration-time curves for ketorolac tromethamine 0.5% administered topically (50 mL) and intracamerally, respectively. The ratio of the areas indicated a fraction absorbed of 3.7%. An identical approach was used by Tang-Liu et al. (3) in determining that 2.5% of the instilled dose of levobunolol was absorbed after a topical dose (50 mL of 0.5%), similar in range to other drugs administered topically.

b. Rate of Absorption. The loss of drug from the precorneal area is a net effect of tear secretion, drainage, and noncorneal and corneal absorption rate processes. When drug concentration in aqueous humor is described biexponentially, the latter, shallower log-linear slope represents elimination out of the eye, whereas the steeper slope is the net effect of the precorneal processes. Because the drainage rate is approximately 100 times more rapid than ka (44,46), it is correct to assign the more shallow log-linear slope from aqueous humor concentration-time curves as elimination from aqueous humor. Consequently, estimation of the steepest slope and subsequent calculation of ka can be obtained from nonlinear curve-fitting techniques if the other precorneal processes are known.

Table 2 lists drugs for which ka has been estimated. These values, when interpreted as half-lives, show how slowly drug is actually absorbed across the cornea. Because of the very rapid loss of drug from the precorneal area, and in particular the drainage rate, it is not surprising to find that only a small fraction of the instilled dose is actually absorbed across the cornea. In addition, the cornea is relatively thick, variable in hydrophilic/lipophilic properties for each layer, and small in surface area. These factors, along with the rapid precorneal loss rate, combine to have a significant effect on the time to peak following topical instillation of drugs to the eye regardless of the drug's physicochemical properties or its elimination rate from internal eye tissues. In general, the time to peak is 20-60 minutes for nearly all ophthalmic drugs when instilled topically to the eye. This has been shown by Makoid and Robinson (27), who determined the ophthalmic pharmaco-

Drug |
ka (min ^ |
¿1/2 (h) |
Ref. |

Pilocarpine |

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