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Drug targets

drug targets and drug transporters

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Drug targets

  1. 1. DRUG TARGETS: Targeted drug delivery is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. Objective: • Provide therapeutic concentration of drugs at the site of action • Reduce systemic toxicity • Increase patient compliance • This improves efficacy of the drug while reducing side effects. Classification of Drug Targeting Drug targeting has been classified into three types: First Order It refers to restricted distribution of the drug-carrier system to the capillary bed of a predetermined target site, organ or tissue. Compartmental targeting in lymphatics*, peritoneal cavity, cerebral ventricles, lungs, joints, eyes, etc. Second Order The selective delivery of drugs to a specific cell type such as tumor cells and not to the normal cells is referred as second order drug targeting. The selective drug delivery to the Kupffer cells in the liver** exemplifies this approach. Third Order The third order targeting is defined as drug delivery specifically to the intracellular site of target cells. The receptor based ligand-mediated entry of drug complex into a cell by endocytosis, lysosomal degradation of carrier followed by release of drug intra- cellularly or gene delivery to nucleolus is an example for this approach. Drug Targeting Principal schemes of drug targeting currently investigated in various experimental and clinical settings include: • Direct application of the drug into the affected zone (organ, tissue) • Passive accumulation of the drug through leaky vasculature (tumors, infarcts, inflammation)
  2. 2. • ‘physical’ targeting based on abnormal pH and / or temperature in the target zone, such as tumor or inflammation (pH- and temperature-sensitive drug carriers) • Magnetic targeting of drugs attached to paramagnetic carriers under the action of external magnetic field • Use of vector molecules possessing high specific affinity toward the affected zone The parameters determining the efficacy of drug targeting: • Size of the target • Blood flow through the target • Number of binding sites for the targeted drug/ drug carrier within the target • Number and affinity of targeting moieties Passive targeting approaches: Pathophysiological factors – Inflammation, Infection, EPR effect Physicochemical factors – Size, Molecular weight Anatomical opportunities – Catheterization, Direct injection Chemical approaches – Prodrugs, Chemical delivery systems Active targeting approaches: Carrier specificity can be enhanced, through surface functionalization with site- directed ligands which bind or interact with specific tissues Biochemical targets – Organs, Cellular, Organelles, Intracellular Physical/External Stimuli – Ultrasound, Magnetic field
  3. 3. Main Approaches to Targeting: Retrometabolic Systems: Individual drug molecules chemically modified to target particularly to the disease site. Carrier – Based Systems: Drug is first packaged non-covalently into a synthetic Carrier that is then targeted to the disease site. Drug Targeting: Prodrugs Compounds that undergo biotransformation prior to exhibiting pharmacological effect Overcoming Barriers Chemically linking pro-moiety to form prodrug  Biotransformation  Release of parent drug  Barrier is circumvented Examples: 6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active morphine in vivo. Prednisone, a synthetic cortico-steroid drug, is bioactivated by the liver into the active drug prednisolone.
  4. 4. Drug Targeting: Magnetic Drug Targeting • Using magnetic nanoparticles (ferrofluids) • Enhancing efficacy • Minimum side effects • Ferromagnetic element (e.g. an implant) is placed in a magnetic field, it becomes magnetically energized Advantages Magnetic drug targeting is used to treat malignant tumors loco-regionally without systemic toxicity. Magnetic particles used as “carrier system” for a variety of anticancer agents, e.g. radionuclides, cancer – specific antibodies, and genes Drug Targeting: LIPOSOMES These are vesicular concentric structures, range in size from a nanometer to several micrometers, containing a phospholipids bilayer and are biocompatible, biodegradable and non immunogenic.
  5. 5. Liposomes have generated a great interest because of their versatility and have played a significant role in formulation of potent drugs to improve therapeutics. Enhanced safety and efficacy have been achieved for a wide range of drug classes, including antitumor agents, antiviral, antimicrobials, vaccines, gene therapeutics etc. DrugTargeting:TransdermalApproach Transdermal drug delivery system is topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. A transdermal drug delivery device, which may be of an active or a passive design, is a device which provides an alternative route for administering medication. These devices allow for pharmaceuticals to be delivered across the skin barrier. Transdermal Approach Continuing: In theory, transdermal patches work very simply. A drug is applied in a relatively high dosage to the inside of a patch, which is worn on the skin for an extended period of time. Through a diffusion process, the drug enters the bloodstream directly through the skin.
  6. 6. Since there is high concentration on the patch and low concentration in the blood, the drug will keep diffusing into the blood for a long period of time, maintaining the constant concentration of drug in the blood flow. Drug Targeting: Brain targeted drug delivery system The brain is a delicate organ, and evolution built very efficient ways to protect it. The delivery of drugs to central nervous system (CNS) is a challenge in the treatment of neurological disorders. Drugs may be administered directly into the CNS or administered systematically (e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain substance. Conclusion Research related to the development of targeted drug delivery system is now a day is highly preferred and facilitating field of pharmaceutical world. It has crossed the infancy period and now touching height of growths from the pharmacy point of view. Targeted delivery of drugs, as the name suggests, is to assist the drug molecule to reach preferably to the desired site. The inherent advantage of this technique has been the reduction in dose & side effect of the drug. Overall it may be concluded with the vast database of different studies, the science of site specific or targeted delivery of these drugs has become wiser. Manifestation of these strategies in clinical now seems possible in near future. DRUG TRANSPORTERS: Introduction Transporters are those proteins that carry either endogenous compounds or xenobiotics across biological membranes.
  7. 7. They can be classified into either efflux or uptake proteins, depending on the direction of transport. The extent of expression of genes coding for transport proteins can have a profound effect on the bioavailability and pharmacokinetics of various drugs. Additionally, genetic variation such as single-nucleotide polymorphisms (SNPs) of the transport proteins can cause differences in the uptake or efflux of drugs. In terms of cancer chemotherapy, tumor cells expressing these proteins can have either enhanced sensitivity or resistance to various anticancer drugs. Transporters that serve as efflux pumps on a cell membrane can remove drugs from the cell before they can act. Transport proteins that are responsible for the vital influx of ions and nutrients such as glucose can promote growth of tumor cells if overexpressed, or lead to increased susceptibility for a drug if the transporter carries that drug into the cell. Importance of Drug Transporter Role in overall disposition of drugs to the target organs Significant determinant of drug-drug interaction Variability in drug response Types of drug transporter Two types of transporter : ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer. Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged Comparison ATP Binding Cassette Solute Carrier Efflux transporter Influx / bidirectional transporter Utilize energy from ATP Electrochemical gradient / facilitated diffusion
  8. 8. Primary active Secondary active Subfamilies : ABCA, ABCB, ABCD, ABCE, ABCDF, ABCG Subfamilies ; SLC15, SLC22, SLCO P-glycoprotein • ATP binding cassette sub family B member-1 (ABCB 1) • Multidrug resistance protein 1 (MDR1) • Transport various molecules, including xenobiotic, across cell membrane • Extensively distributed and expressed throughout the body Function of P-glycoprotein Site of transportation Function Liver – Bile Elimination Kidney - Urine Excretion Placenta – Maternal blood Protect fetal from drug exposure Intestine – Intestinal lumen Reduce drug absorption into the blood Brain – Blood Monitor drug access to the brain Mechanism of P-glycoprotein ① Substrate bind to P-gp form the inner leaflet of the membrane ② ATP binds at the inner side of the protein ③ ATP is hydrolyzed to produce ADP and energy ④ Substrate is excreted outside the cell
  9. 9. Clinical Importance P-gp is a multidrug resistant protein (MDR) Role of P-gp is significant in tumor cells. Expression of P-gp in tumor cells reduces the accessibility of cytotoxic drugs by eliminating them in various pathways. Hence, P-gp may act as a major barrier to effective drug treatments. Over expression of P-gp in limit the treatment for cancer, AIDS, Alzheimer’s and epilepsy. References Dean M, Hamon Y, Chimini G (July 2001). "The human ATP-binding cassette (ABC) transporter superfamily” Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004). "The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins: Introduction” Dean, Michael (2002-11-01). "The Human ATP-Binding Cassette (ABC) Transporter Superfamily” Peter N Bennett, Morris J Brown, Pankaj Sharma, 11th Edition (2012). “Clinical Pharmacology” Department of Drug Metabolism, Merck Research Laboratories (Nov 2003). “Clinical relevance of P-glycoprotein in drug therapy”

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