The integrin receptors, alpha v beta 3/5 (αvβ3/5), have been implicated in the promotion and maintenance of tumor angiogenesis and are important for tumor cell invasion and migration. EMD138444 is a low-molecular-mass peptide which was designed and tested as a specific antagonist of the αvβ3/5 receptors. When the pharmacokinetic profile of this compound was assessed in animals, avid hepatic extraction and accumulation in the liver was noted. Accordingly, it was hypothesized that drug uptake transporters may be responsible for the observed hepatic uptake of EMD 138444. Utilizing a recombinant vaccinia system, an array of uptake transporters known to be expressed in the liver, such as members of the organic anion transporting polypeptide (OATP) transporter family, as well as the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP), was heterologously expressed in HeLa cells. The role of P-glycoprotein (P-gp) in the biliary excretion of this compound was also assessed using polarized epithelial cell lines LLC-PK1, L-MDR1, and Caco-2. Certain members of the human as well as rat OATP transporters such as human OATP1B1 (OATP-C), OATP1B3 (OATP-8), OATP1A2 (OATP-A), and rat Oatp1b2 (Oatp4), were capable of mediating the cellular uptake of EMD138444. We have previously reported the existence of functionally deleterious polymorphisms in the human OATP1B1 gene. Two common polymorphisms in OATP1B1, T521C (Val174Ala) and G1463C (Gly488Ala), with approximate allele frequencies of 14% in European-Americans and 9% in African-Americans respectively, were associated with significantly impaired transport capacity for EMD138444 in HeLa cells when compared to wild-type OATP1B1*1a or *1b. However, cell lines expressing P-gp did not reveal any differences in the basal-apical versus apical-basal transport of EMD138444, suggesting that this compound is not a substrate for P-gp. Thus, drug uptake transporters, particularly members of the OATP transporter family, appear to be key transport systems involved in the hepatic uptake of the αvβ3/5 receptor antagonist EMD138444. Given the broad substrate specificity of OATP transporter family members, inclusion of uptake transporters as a potential determinant of drug disposition may aid in the design of targeted therapeutics with more favorable disposition profiles. Incorporation of pharmacogenetic analyses in clinical trials may aid in explaining the large interpatient variation in pharmacokinetic parameters often seen during evaluation of investigational agents or approved chemotherapeutic agents.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]