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aC10 calculated from Eq. 4-6 in text.

aC10 calculated from Eq. 4-6 in text.

drugs, referred to as "soft drugs,'' are designed for rapid metabolism and subsequent conversion to an active species before being eliminated from the eye. For example, an adamantylethyl of metaprolol has shown a prolonged and greater reduction of IOP and also a reduced potential to cause tachycardia when compared to timolol in the rabbit eye (103). In another example, timolol maleate was oxidized to a keto analog and coupled with either hydroxylamine or methoxyamine. The resulting drug candidates, timolone oxime and timolone methoxime, showed greater reduction of IOP than timolol in rabbits administered the drugs topically and did not show cardiovascular effects when administered intravenously to rabbits or rats (104).

Many enzyme systems have been identified within ocular tissues. As summarized by Plazonnet et al. (15), these are catechol-O-methyltransferase, monoamine oxidase, steroid 6-betahydroxylase, oxidoreductase, lysosomal enzymes, peptidases, glucuronide and sulfate transferase, and glutathione-conjugating enzymes. Arylamine acetyltransaferase activity was demonstrated by Campbell et al. (106) in an anterior chamber tissues using p-aminobenzoate, aminozolamide, and sulfamethazine as substrates. The rank order of arylamine acetyltransferase activity regardless of substrate was liver > iris/ciliary process > corneal epithelium > stroma/endothe-

lium. Although fast- and slow-acetylating rabbits, classified with respect to their rate of hepatic acetylation, metabolized aminozolamide at different rates in liver tissue, no differences between phenotypes were observed for aminozolamide either in ocular disposition or in decline of IOP following topical instillation.

The distribution of ketone reductase activity in anterior chamber tissues was determined by Lee et al. (107) in order to explain the metabolism of levobunolol to dihydrolevobunolol. The rank order of activity was corneal epithelium > iris/ciliary body > conjunctiva > lens. No activity was detected in the tears, corneal stroma, sclera, or aqueous humor. Bovine ciliary body apparently contains aldehyde oxidase, which is responsible for the reduction of a number of compounds: N-oxide, hydroxamic acid, and sulfoxide and nitro compounds (108).

Metabolic models have been devised for ketanserin (52) and levobu-nolol (3) (Fig. 7). It is important to study ocular metabolism so that drug disposition is better understood and also in anticipation of a new drug candidate. For example, an endogenous corneal epithelial arachidonic acid metabolite formed by the cytochrome P450 system and a potent inhibitor of Na + -K + -ATPase was found to significantly lower IOP in the rabbit eye (109).

Figure 7 Metabolic schemes devised for ketanserin and levobunolol following absorption in the eye. (Adapted from Refs. 3 and 52.)

In general, the iris/ciliary body and the epithelium of the cornea appear to be anterior chamber tissues with the greatest capacity for metabolism.

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