THE ROLE OF TRANSPORTERS IN DRUG THERAPY
Introduction.
Phase I and II do not adequately account for variability in drug response and removal. Transporters are being regarded to have significant roles in drug absorption, distribution and excretion. Therefore, transporters must be considered seriously in the analysis and prediction of drug absorption removal and pharmacodynamics.
Major Classes of Drug Transporters
Drug transporters are classified according to the International Union of Biochemistry and Molecular Biology in the Transporter Classification Database giving 9 major classes. The major drug transporters involved in drug absorption, distribution and excretion belong to 2 super-families ABC (ATP-binding cassette) and SLC (Solute-linked carrier) involved in both cellular uptake and efflux.
Drug transporters are critical determinants of drug efficacy and toxicity. For instance, transporters in the gastro-intestinal tract affect drug absorption by increasing uptake (uptake transporters) or by limiting drug absorption (efflux transporters). Alternatively the P-gp transporters in the blood-brain barrier prevent drugs from entering the central nervous system by efflux mechanisms.
The truth is drug transporters might be responsible for some of the unexplainable variations encountered in drug absorption and excretion.
Variations in transporter systems are possible because being or containing proteins which are coded for in genes. These genes are susceptible to mutation thus affecting the structure and function of transporter systems, just like metabolizing enzymes polymorphism is real in drug transporter systems and this should be adequately considered in drug absorption, distribution and excretion analysis especially for drugs under going trials.

Drug Absorption and Distribution.
Inhibition of transporters can affect drug absorption and/or distribution to different sites. For example the transporter P-gp through efflux mechanism reduces drug distribution across the blood brain barrier. Similarly the transporter OATP monitors or limits drug distribution to the liver. The clinical implications for drug administration are that concomitant use of other drugs that activate or inhibit these transporters may affect distribution of the other drug. A frequently cited example is that of quinidine, an inhibitor of P-gp; when quinidine is co-administered with loperamide, the former inhibit P-gp and allows higher concentrations of loperamide to cross the blood-brain barrier, which can lead to dangerous neurotoxicity including respiratory depression.
Drug Metabolism and Excretion.
Drug metabolism is the primary mechanism by which drugs are converted to their metabolites. It is important the effect of metabolism on some drugs that are converted to pharmacologically active metabolites or in some cases, into reactive, toxic, and carcinogenic metabolites. Transporters play a vital role here by mobilising drug molecule away from (efflux transporters) or towards the site of metabolism (uptake transporters). Polymorphism in transporters can affect drug metabolism as the presence and the quantity of transporter may determine the rate and amount of drug molecules to the site of metabolism.
Since most drugs are substrates, inhibitors or inducers of both metabolising enzymes and transporters, metabolism may affect transport and vice-versa when enzymes and transporters have close physical proximity. For example both P-gp and CYP3A4 are expressed in intestinal enterocytes, and both these proteins have common substrates. Hence, this proximity can limit drug bioavailability either by intestinal first-pass metabolism of the drug via CYP3A4 or by P-gp-mediated efflux of the drug. These interactions have important clinical implications when co-administering different effects on transporters and metabolising enzymes
Pharmacodynamics
The effect of drugs can be greatly affected by drug transporter systems as drugs with excellent pharmacokinetics parameters may not have an effect that is commiserate because some transport systems efflux drug molecules away from receptor sites and this leads to less activity of the receptors.
Also, some areas in the body can ‘trap’ drug molecules making them less available at the required receptor sites due to the effect of transporters ‘influxing’ drug molecules into these areas
Conclusion.
The importance of drug transporters is becoming increasingly obvious in Pharmacokinetics and Pharmacodynamics of xenobiotics. These roles can be studied in-depth to and can be exploited to our advantage as scientists or considered in drug dosing and formulation.
References
Guengerich, F. P. (1997). “Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species.” Chem Biol Interact 106(3): 161–82.
Salyers, K. L. and Y. Xu (2012). Animal Models for studying drug metabolising enzymes and transporters. ADME-Enabling Technologies in Drug Design and Development. D. Zhang and S. Surapaneni, John Wiley & Sons, Inc.
Ogunbona, F. A., Onyeji C. O., Bolaji, O. O. and Adedoyin A., (2014). Pharmacokinetics: Principles And Application. Ibadan University Press.
Lei Zhang, John M. Strong, Wei Qiu, Lawrence J. Lesko, and Shiew-Mei Huang (2006); Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions
