Biomedical Engineering Reference
In-Depth Information
aqueous humor, iris, and ciliary body with lower concentrations in
the lens and vitreous humor [
2
]. Due to extensive vascularization of
the iris and ciliary body, this often results in efficient drug clearance
from those tissues [
2
,
6
]. However, the vitreous humor, which
occupies approximately 80 % of the eye volume in humans, has
very low turnover. If the drug is successful in reaching the vitreous
humor, this fluid can act as a reservoir to continuously deliver
administered drug over an extended period of time to other eye
tissues, especially the retina. Therefore it is necessary to know the
drug concentration and the time course in applicable individual eye
tissues to assess whether the drug is reaching the assumed site of
action and in sufficient quantities to be efficacious. Lack of efficacy
of a drug with known biological activity after ocular or systemic
administration may simply be due to poor ocular distribution and/or
ocular biotransformation of the drug to inactive metabolites.
After entry into eye tissues, the drug may undergo rapid con-
version to inactive metabolites, effectively lowering drug-mediated
responses [
1
,
2
]. There is ample documentation in the literature
that the eye contains “detoxifying enzymes” for protection against
continuous exposure to foreign substances [
7
-
14
]. Although pres-
ent in much lower levels than in the liver, cytochrome P-450
[
15
-
21
], monoamine oxidase [
22
,
23
], and diamine oxidase [
24
]
activities have been reported in ocular tissues. Aldehyde dehydro-
genases are reported to be highly expressed in the cornea [
25
].
Esterases, including acetylcholinesterase and butyrylcholinesterase,
are abundant in eye tissues [
26
-
29
] and may even be elevated in
inflamed tissue [
30
]. Additionally, oxidoreductase activities have
been reported [
31
-
34
]. Phase II (conjugating) enzymes present
in ocular tissues include glutathione-S-transferases and UDP-
glucuronosyltransferases [
35
,
36
]. A number of drug transporters
are also present in ocular tissues. These transporters, some of which
are highly expressed, may also play a significant role in ocular drug
absorption or lack thereof [
37
]. While many of the drug-
metabolizing enzymes will not have significant activity in collected
ex vivo samples, some of the enzymes, such as the esterases,
can remain active post sample collection. Such activity can have
considerable impact on final drug concentration determinations
and must be considered in the development of suitable bioanalytical
methods. While metabolic degradation can result in significant
losses of drug, these same processes also can be exploited using a
pro-drug approach. Pro-drugs, with little or no biological activity,
can have superior drug absorption and distribution characteristics
over their metabolically or chemically generated active drugs. These
characteristics may be exploited to facilitate delivery of the pro-
drug to the target sites within the eye where it is converted to the
active drug at adequate concentrations leading to a desired
biological response. Examples of pro-drugs used successfully in
ocular
indications
include latanoprost and travoprost
[
38
].
