SAL1 Pharmacogenomics and drug discovery: Impact of transporter-mediated disposition and interaction in chemotherapy

Speakers' Abstracts/International Journal of Antimicrobial Agents 26S (2005) S1 $63 round for proposals, countries need to assess their absorptive capacity to implement more projects, plan their technical assistance, and learn from their previous grant implementations.

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F5 1st Forum 1.5. The economic burden of tuberculosis Pieter Johannes VAN MAAREN. Western Pacific Regional Office of the

World Health Organization, Manila, Phihppines F4 1st Forum 1.4. The Philippine Partnership to Fight Tuberculosis, Malaria and AIDS Myrua C. CABOTAJE. Philippines Country Coordinating Mecku;nism,

Manila, Phihppines Tiffs forum launches tile Plfilippine Partnership to Fight TB, Malaria and AIDS. The 1st forum is undertaken to consolidate, maintain and increase partners' political commitment to the objectives of the Partnership; to create and exploit opportunities for advocacy; to review overall progress, identify problems and new challenges and exchange infomlation; mid to nominate representatives of various sectors for membership to tile Country Coordinating Mechanism (CCM). The Partnership is a network of national partners, international pub lic and private donors, government and non governmental organizations 0NGO) and academic institutions committed to fight TB, malaria and AIDS so that these will cease to be public health problems in tile Plfilippines. Tile four-point mission consists of: (1) Ensuring access of all patients with TB, malaria Hid HIV/AIDS to effective diagnosis, treatment and cure; (21) Stopping transmission of TB, malaria Hid HIV/AIDS; (131) Reducing the social and economic toll of TB, malaria and HIV/AIDS; and (4) Advocating for new diagnostic, therapeutic and preventive tools and strategies to eliminate TB, malaria and H1V/AIDS. The strategies for control axe closely linked with poverty alleviation programs of tile government. Tile strategies include: strengtheaing partneizliips with DOH and tile LGUs; expanding and ensuring the quality of the currently available interventions against TB, malaria and HIV/AIDS; addressing emerg ing challenges like multi drag resistant TB and malaria and H1V/TB co-infection; and applying emerging appropriate and cost-effective technologies. For tile Plfilippines, tile big burden of MDR-TB necessitates tile integration of DOTS-Plus into the NTP program and tile aggressive implementation of proven preventive strategies including condom usage to maintain the low (< 1%1) prevalence of H1V/AIDS. The CCM is a partnership involving a broad range of stakeholders that builds on existing mechanisms for planning control programs at tile national level. It represents and acts on behalf of tile Partnership. Established in March 5, 2002, tile CCM is a stand-alone committee that emanated from tile expansion of tile National Infectious Disease Advismy Committee (NIDAC) through Administrative Order No. 83 A s. 2002. It coordinates the development of proposals to the Global Fund to fight AIDS, TB, Malaria (GFATM), submits proposals for the country, monitors tile implementation of activities of tile GF projects, and elects tile Principal Recipient responsible to tile GFATM for project implementation. Pemlanent members of tile CCM include: tile Department of Health, the World Health Organization, UNAIDS and persons living with AIDS. Rotating members include: other government agencies, private sector representatives, NGOs, corporate foundations, public private coalitions, faith-based organizations, and other bilater0Mmultilateral development partners. "vVithtile nomination for membersllip from tile different sectors as output of tile 1st Forum of tile Partnersliip, tile membersllip of tile CCM will be selected by their constituents in a transparent and democratic manner, as recommended by the GFATM.

TB has a strong economic impact because of its high prevalence and because 75% of TB cases are in the economically productive age group of 15 54 years. The economic cost of TB includes the operational costs for national TB programs, which is estimated to be USD 2 billion annually in less developed countMes; mlother USD 250 nfillion is spent for research on new vaccines, diagnostic tools and drugs. In addition, poor TB control leads to adverse consequences for tile country due to loss of potential tax revenue from loss of healthy and productive years of its citizenry and loss due to rising health service costs. The invisible costs of TB are estimated at USD 1 billion due to reduced productivity of 9 million TB cases per year mid another USD 11 billion due to tile loss of 15 years income from 2 million deaths annually. Hence tile mlnual loss attributed to TB is estimated to be USD 12 billion. Tile patients' direct costs include transport, user fees and food, while indirect costs include loss of income, loss of household work due to TB in women, and psyehosocial costs. The costs incurred by the public health service include investment and operational costs to cover facilities, personnel, drugs, equipment and supplies. Tile costs incui:red due to poor TB control will inevitably increase yeas after year. Tile costs of DOTS are approximately USD 30-40 per death averted and approximately USD 1-3 per DALY (disability-adjusted life yeas). Hence DOTS is considered by the World Bank as one of the most cost effective health interventions available. Several studies show that for every US dollar invested in DOTS, there is a return to the country of five US dollars. Tile impact of DOTS is greatest where tile detection of cases occurs eaxly, when it replaces a poor program with low cure rates, Hid when introduced in young populations. In conclusion, poor TB control is costly to the country as it leads to loss of economic productivity and high costs to address the problem. It is also costly to the community as a result of loss of income as well as financial and psychosocial costs. DOTS is economically beneficial because of reduced costs for health services and reduced costs for TB patients. Its long-teml benefits are higher economic productivity for tile country and healtliier lives for patients.

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State-of-the-Art

Lectures

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Pharmacogenomics and Drug Discovery: Impact of Transporter-mediated Disposition and Interaction in Chemotherapy Akira TSUJI. Kanazawa University, Kakuma-maehi, Kanazawa, Japan

Introduction: Membrane transports of synthesized drugs have long been believed to proceed by a simple diffusion depending on the lipophilic nature of the drug molecules. However, it has recently been well recognized that drug transporters play pivotal roles in determining tile pharmacoldnetic profiles of particulax drugs and thereby detelanine tile overall phamlacological effects, i.e., drug absorption, distribution, elimination and concentration at the target sites. In the past decade, a compmhenaive list of membrane transporters has become available owing to the progress in genome analysis, as well as extensive membrane physiological and moleculax biological studies on membrane transporters. Major membrane transporters have been classified into tile solute carrier (SLC) transporter family and tile ATP-binding cassette (ABC) trmisporter. The SLC family consists of 40 gene sub families and a total of 319 family members, including ion coupled transporters, facilitated transporters and exchangers (URL: http://www.bioparadims.org/slc/intro.asp). In the ABC trans porter fmnily, 48 genes have been identified and classified into seven

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Speakers' Abstracts/International Journal of Antimiorobial Agents 26S (2005) S1 $63

subfamilies (URL: http://www.gene.ucl.ac.uk./nomenclatureD. Some of these transporters accept not only physiological or endogenous substrates, but also drugs, including antimicrobial agents such as ~ lactam antibiotics and new quinolones. This lecture aims to provide clues that will allow us to establish efficient atrategies to use transporters for personalized therapy and lead discovery of orally effective antimicrobial agents.

Transporter-Mediated Pharrnacokinetics of I]-Lactam Antibiotics: There are orally effective peptide mimetic drags, such as ~ lactam antibi otics, ACE inhibitors, anti cancer agent bestatin and antivirus valacyclovir, wliich are absorbed via a proton-coupMd oligopeptide transporter human PEPT1 expressed in tile apical membrane of intestinal cells. Human PEPT2, cloned as a homologue of PEPT1, is expressed only at tile apical membrane of renal epithelial cells and participates for reabsorption of several ~ lactam antibiotics from urine. Plasma peak time and AUC normalized by the dose after oral administration of 5 mg,'kg ocfadroxfl in humans was significantly delayed mid decreased, respectively, with co-administration of 15 mg/kg cefalexin, presumably due to tile competitive inhibition of tile intestinal PEPTl-mediated transport of cefadroxil by cefalexin. The 70% increased absorption rate and 25% increase in the bioavailability of 1 g amoxicfllin with co administration of 20 nag nifedipine in humans are considered to be attributable to the increase of tile proton concentration at tile apical surface of epithelial cells as tile driving fmce for amoxicillin transport via PEPT1. Several ~-lactam antibiotics in tile blood are transported via m~ganic anion transporters, OAT1-3 expressed at tile basolateral menlbrane of the proximal tubule. They are excreted into urine via OAT4 expressed at the apical membrane. NPT1 (NaPi 1), which has been cloned as the renal inorganic phosphate transporter in rats, rabbits, and humans, and expressed at tile apical membrane of renal epithelial cells and at hepatic sinusoidal membrane. NPT1 transports several organic anions such as benzyl penicillin, fm'openem, probenecid, phenol led mid several organic anions into urine. We have previously demonstrated that ~ lactam antibiotics are taken up by hepatocytes and excreted into bile via multiple organic anion transporters. Cefoperazone is transported by MRP2, one of ABC transporters and therefore excreted mainly into bile rather than into urine. Tile tissue distribution and transporting function of organic anion transporting polypeptide OATP families, OAT2, NPT1 mid MRP2 suggest that these transporters may regulate tile uptake from tile blood stream into hepatocytes and biliary secretion of ~ lactam antibiotics. Since the transport activity of NPT1 is reduced by a high concentration of chloride ion, it is supposed that NPT1 may function for the efflux of organic anions such as ~-lactam mltibiotics from hepatocytes to blood across tile sinusoidal membrane. Transporter-Mediated Pharmacokinetics of New Quinolones: Fluoroquinolone antimicrobial agents (NQ) exhibit distinct pharmacokinetic features. For example, grepafloxacin (GPb~X) and HSR 903 were devel oped with the objective of being used for respiratory and biliary duct infections. Both NQs actually exhibit liigher distributions to tile various tissues, i.e., lung mid liver, and greater hepatobiliary transport, compared with tile other NQs. Tile membrane transport processes such as an active influx and/or efflux in the liver contribute to a greater hepatobiliary exeretion of GPFX and HSR 903. Transporters that recognize both organic anions and cations are involved in the hepatic uptake of two NQs whereas tile efflux to tile bile is at Mast partially mediated by MRP2. Regarding tile urinary excretion of NQs, P-glycoprotein (P-gp), a MDR1 gene product, and some other influx transport system play a roM in tile lena/ tubular secretion of NQs. These findings could imply that active transporters should be one of the important factors that deten-nine the elimination route, i.e., biliary or urinary excretions, of NQs from the systemie circulation. Regarding tile tissue diatiibution profiM, tile phacmacokinetic studies using rmJrl gene-knockout mice have revealed that tile diatiibution of relatively lipoptfilic NQs such as GPFX, HSR-903 and spaz'floxacin to tile brain is restricted because of the limited permeability of these compounds through the blood brain barrier by P gp. In addition to the efflux by P gp, the involvement of MRP1 has been reeenfly clarified in the tissue distribution of several NQs using mrpl gene-knockout mice, and MRP1

seems to be involved as an efflux system in several tissues including kidney, heart and skin. The active efflux transporters may also be involved in the gastrointestinal absorption of NQs such as GPFX, HSR 903 and sparfloxacin have been reported to be actively secreted across the apical membrane of tile intestinal epithelial cells, mid P-gp possibly limits tile bioavailability in vivo. Rifampicin-Mediated Drug Interaction: A number of clinically important drug interactions with rifampin have been reported that are caused by its powerful induction of intestinal cytochrome P450 3A4 and P gp. Recent findings, however, indicated that concomitant administration of rifampin at a dose of 600 mg/day for 10 days in healthy volunteers educed digoxin plasma concentrations substantially after an oral single-dose (1 mg) administration by comparing tile plasma-time profiM without iifampin treatment. The effect was less pronounced after intravenous administration of digoxin. The oral bioavailability of digoxin decreased by 30% during rifampin therapy. When duodenal biopsies from each volunteer before and after administration of iifampin were analyzed, iifampin treatment increased tile content of intestinal P-gp, 3.5±2.1-fold, which con'elated well with tile area under tile curve (AUC) after oral digoxin but not after intravenous digoxin. Since rifampin is a known inducer of cytochrome P450 enzymes (:e.g. CYP3A4) as web as P gp, the induction of intestinal CYP3A4 protein may increase intestinal metabolism, predicting a decrease of plasma digoxin level after rifmnpin treatment. Although the CYP3A in duodenal sampMs was enhmlced 4.4-fold, there was no correlation between tile AUC of digoxin and CYP3A4 expression of tile individual volunteer. These data atrongly indicate that P-gp modulates intestinal digoxin abanlption, leading to low drug concentration in individuals with high P gp expression and high concentrations in those with low P gp expression. Accordingly, rifampin mediated P gp induction is associated with a reduction of plasma digoxin. Digoxin is absorbed from the intestine in tile extent of ca. 70% and eliminated from tile body mainly by glomerulm" filtration; P-gp-mediated tubular secretion of unchanged drug and its metabolism is negligible. Indeed, digoxin has been identified by experiments with in vitro MDR1 expressing cukure ceBs and mdrla knockout mice as a substrate of renal intestinal and blood brain barrier P gp. Conelusimls: Being recognized by SLC and ABC transporter families mid tile other unknown transporters, drugs including antimicrobial agents exliibit specific phamlacokinetic profiM of each compound. Since the pharmacokinetic features are closely related to the pharmacological activity and adverse effects in vivo, the research on membrane transport mechanisms could produce new compounds with distinct pharmacokinetic features, leading to tile new concept for drug research and development. Drug-drug interactions and generic polymorphisms of drug transporters as well as metabolizing enzymes may alter phacmacokinetics of drugs, triggering inte~individual differences in the efficacy and safety of drug therapy.

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Applications of Pharmacodynamics in Drug Development: New and Older Agents William A. CRAIG. University of Wisconsin Medical School, Madison,

WI, USA Phamlacodynamics measures the relationslfips between a drug's phaxmaeokineties and the time course of its antimicrobial activity. Marked differences among antimierobials have been observed in the time course of antimierobial activity. For example, higher concentrations of beta lactanl mltibiotics do not kill1 bacteria faster than lower concentrations and regrowth begins very soon after drug levels fall below tile minimal inhibitory concentrations (MIC). On tile other hand, aminoglycosides and quinolones produce concentration dependent killing of bacteria and can induce prolonged persistent effects with both Gram negative bacilli and Gram positive cocci. Because of these diffemnocs in pharmodynamie activity, tile pharmacoldnetic/pharmacodynamic (PK/PD) indices that de-