Multiple new small molecules such as tyrosine kinase, mammalian target of rapamycin (mTOR) and proteasome inhibitors have been approved in the last decade and are a considerable progress for cancer therapy. Drug transporters are important determinants of drug concentrations in the systemic circulation. Moreover, expression of drug transporters in bloodtissue barriers (e.g. bloodbrain barrier) can limit access of small molecules to the tumour (e.g. brain tumour). Finally, transporter expression and (up)regulation in the tumour itself is known to affect local drug concentrations in the tumour tissue contributing to multidrug resistance observed for multiple anticancer agents. This review summarizes the current knowledge on: (i) small molecules as substrates of uptake and efflux transporters; (ii) the impact of transporter deficiency in knockout mouse models on plasma and tissue concentrations; (iii) small molecules as inhibitors of uptake and efflux transporters with possible consequences for drugdrug interactions and the reversal of multidrug resistance; and (iv) on clinical studies investigating the association of polymorphisms in genes encoding drug transporters with pharmacokinetics, outcome and toxicity during treatment with the small molecules.

Background and purpose:Organic anion transporting polypeptide 1B3 (OATP1B3) (SLCO1B3) mediates the uptake of endogenous substrates (e.g. estrone-3-sulphate) and drugs (e.g. pravastatin) from blood into hepatocytes. Structure-based modelling of OATP1B3 suggested that a pore with a positive electrostatic potential contributes to the transport mechanism. Therefore, we investigated the role of conserved positively charged amino acids for OATP1B3-mediated uptake of sulphobromophthalein (BSP) and pravastatin.Experimental approach:Residues Lys28, Lys41 and Arg580 in OATP1B3 were substituted by alanine, arginine, glutamine, glycine or lysine. Using immunofluorescence, immunoblot analysis and cellular uptake assays, the effect of these mutations on protein expression and transport activity was investigated.Key results:Immunofluorescence revealed that all mutants were localized in the plasma membrane with partial intracellular retention of the Arg580 > Ala and Arg580 > Lys mutants. Lys41 > Ala, Lys41 > Gln, Lys41 > Gly, Arg580 > Gly and Arg580 > Lys showed significantly reduced transport for BSP and pravastatin. Kinetic analyses of BSP transport revealed a significant reduction of V-max normalized to cell surface protein expression for Lys41 > Ala (wild type: 190 +/- 8, Lys41 > Ala:16 +/- 4 pmol (mg protein)-1 min-1, P < 0.001), whereas V-max of Lys41 > Arg and Arg580 > Lys (103 +/- 8 and 123 +/- 14 pmol (mg protein)-1 min-1, P > 0.05) did not change significantly. This suggests that the positive charges at positions 41 and 580 are important for transport activity of BSP. Structural modelling indicated that the positively charged side chain of Lys41 is flexible within the pore. The orientation of Arg580 is defined by adjacent residues Glu74 and Asn77, which was confirmed by kinetic analysis of Glu74 > Ala.Conclusions and implications:We demonstrated that the conserved positively charged amino acids Lys41 and Arg580 are pivotal to the transport activity of OATP1B3.

Individualized drug therapy is one important aspect of patient safety. To consider the individual disposition of the target group is essential, as an incorrect dose or wrong frequency of drug administration are common reasons for -preventable -medication errors [1]. In addition, adverse drug reactions are a health care issue affecting many patients [2,3]. Especially in older individuals a high percentage of these effects are regarded as avoidable. Due to age-related physiological changes concerning pharmacokinetics and pharmacodynamics, some drugs are associated with an increased risk for adverse effects in the elderly; this should be kept in mind when choosing the adequate medication for an older person [4]. Other patient groups, e.g. pregnant and lactating women as well as patients with renal or hepatic impairment, also require a therapy tailored to the individual and specific needs to ensure a safe and effective medication use. Children undergoing drug therapy are at special risk, as only limited data is available from clinical trials (which are mostly performed in adults), and off-label use is common [5]. Furthermore, inter-individual variability due to genetic polymorphisms can play an important role, too. Especially in cancer patients individualization of drug therapy based on the genetic predisposition may reduce toxicity and increase efficacy [6]. In the mentioned context, large-scale pharmacoepidemiological studies are an essential measure to investigate the beneficial or potentially harmful effects related to the use of drugs in different populations. Therefore, conducting more of these studies in the future is not only desirable but highly needed to improve the safety of our patients. References 1. Fanikos et al. Am J Cardiol 2007; 100: 1465--9. 2. Maywald et al. Ann Pharmacother 2004; 38: 2154--9. 3. Huber et al. Pharmacoepidemiol Drug Saf 2009; 18: 111--9. 4. Fick et al. Arch Intern Med 2003; 163: 2716--24. 5. World Health Organization. Promoting Safety of Medicines for Children. Geneva: WHO, 2007. 6. Walko et al. Nat Clin Pract Oncol 2009; 6: 153--62. 2 CHANCES AND CHALLENGES OF GERONTOPHARMACOLOGY M. Wehling Universität Heidelberg, Klinische Pharmakologie Mannheim, Maybachstrasse 14, 68169 Mannheim, Germany