Received for publication February 20, 2008.
Revised April 3, 2008.
Accepted for publication April 7, 2008.

Drug Transporter and CYP P450 mRNA Expression in Human Ocular Barriers: Implications for Ocular Drug Disposition

Abstract

Studies were designed to quantitatively assess the mRNA expression of (1) 10 CYP P450 enzymes in human cornea, iris-ciliary body and retina/choroid relative to their levels in the liver, and of (2) 21 drug transporters in these tissues relative to their levels in human small intestine, liver or kidney. Potential species differences in mRNA expression of PEPT1, PEPT2 and MDR1 were also assessed in these ocular tissues from rabbit, dog, monkey, and human. CYP P450s expression was either absent or marginal in human cornea, iris-ciliary body and retina/choroid, suggesting a limited role for P450-mediated metabolism in ocular drug disposition. In contrast, among 21 key drug efflux and uptake transporters, many exhibited relative expression levels in ocular tissues comparable to those observed in small intestine, liver or kidney. This robust ocular transporter presence strongly suggests a significant role that transporters may play in ocular barrier function and ocular pharmacokinetics. The highly expressed efflux transporter MRP1 and uptake transporters PEPT2, OCT1, OCTN1 and OCTN2 may be particularly important in absorption, distribution and clearance of their drug substrates in the eye. Evidence of cross-species ocular transporter expression differences noted in these studies supports the conclusion that transporter expression variability, along with anatomic and physiological differences, should be taken into consideration to better understand animal ocular PK and PD data and the scalability to human for ocular drugs.

Key words: ABC transporters, active transport, CYP expression, human CYP enzymes, organic anion transport, organic cation transport, transporters