Some important members in drug transporter family

Dear Dixon,
Yes, Insulin stimulate glucose uptake due to presence of insulin-sensitive glucose transporter (GLUT4) to the plasma membrane and most comman site for these transporter is muscle tissue (because they utilize major amout of glucose).
By increase the number of GLUT4 transporters that are functionally inserted in the plasma membrane in muscle and adipocytes may lead to new therapies to treat or prevent non insulin dependant diabetis mellitus(NIDDM).

Reference-
Kahn BB.Glucose transport: pivotal step in insulin action.Diabetes 1996,45(11):1644-54.
Regards,
Amol

Dear Dixon,
GLUT4 gene transcription is regulated by a number of factors in skeletal muscle that include MEF2, MyoD myogenic proteins, thyroid hormone receptors, Kruppel-like factor KLF15, NF1, Olf-1/Early B cell factor and GEF/HDBP1. That can be useful for glucose transport during diabetic conditions.
Reference-
Zorzano A, Palacín M, Guma A. Mechanisms regulating GLUT4 glucose transporter expression and glucose transport in skeletal muscle.Acta Physiol Scand. 2005, 183(1):43-58.
Regards,
Amol

Dear Pragathi,
Transporters are suitable for certain conditions as well as effective, most of the drugs can't able to penetrate through BBB. If one can design drug in a proper way by considering anatomical location of specific transporter, they will definitely operate as per requirement.
Regards,
Amol

Dear Sakshi,
Perticular transporters have different substrates and inhibitors. Based upon the need one can used them alone or in combination like for detoxification in brain region, different drug-drug, food-drug interaction, in cancer etc.
e.g. If one has to increase the penetration of anti HIV drugs to fetus but it should be safe enough, for that drug penetration should incerase in the short period before delivery to minimize the chance that there will be mother-to-child transmission of the virus during birth. According to animal studies, it demonstrated that even oral administration of the P-gp inhibitors PSC 833 (cyclosporin A analog)can substantially increase the fetal penetration of the HIV protease inhibitor saquinavir to levels that suggest placental P-gp was completely inhibited.
There are such lot of examples are there, please refer for details.
References-
A. H. Schinkel, J. W. Jonker. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Advanced Drug Delivery Reviews 55 (2003) 3–29.
J.W. Smit, M.T. Huisman, O. van Tellingen, H.R. Wiltshire, A.H. Schinkel. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J. Clin. Invest 104 (1999) 1441–1447.
Regards,
Amol

Dear Amit,
Might be you are not satisfied with my last answer. Ok, let it be. Here some more factors that should be considered during drug development, these all are risk factors:
1)Lack of predictive preclinical models and inadequate and complex clinical trial designs.
2)Toxicity is severe and poorly predictable. Furthermore, 40% of exits from Phase I trials are caused by inappropriate pharmacokinetics of the test compound.
3)Several investigational new drugs fail in clinical testing because they do not behave pharmacologically as predicted in animal studies.
4)Genetic and molecular mechanisms are most of the time not involved.

If we say in case of anti cancer drugs particularly (success rate is very less in this case by conventional approach):
New animal models with humanized biotransformation systems and drug transporters and animals bearing genetically modified tumors better reflecting human tumor biology and drug disposition (the so-called ‘mouse clinic') could significantly improve the drug development process. By using these models, it is expected that more efficient, faster and less costly drug development is achieved, especially by better preclinical selection of clinical candidates based on more stringent assessment of proof of concept as well as by selection of clinical candidates with better pharmacological profiles and by better definition of the target population of patients during clinical development.

For further details please refer following articles:

1)Wang J, Urban L. The impact of early ADME profiling on drug discovery and development. Drug Discov World. 2004; 73–86.
2)Fox E, Curt GA, Balis FM. Clinical trial design for target-based therapy. Oncologist. 2002;7:401–409.
3)Kummar S, Kinders R, Rubinstein L, Parchment RE, Murgo AJ, Collins J, Pickeral O, Low J, Steinberg SM, Gutierrez M, Yang S, Helman L, Wiltrout R, Tomaszewski JE, Doroshow JH. Compressing drug development timelines in oncology using phase ‘0' trials. Nat Rev Cancer. 2007;7:131–139.

Dear Ritesh,
Studies shown such findings of transporter expression during liver regeneration:
Reduction in the molecular expression of Ntcp, Oatp1 and Oatp2.
Increased expression levels of Mdr1a/b and Mdr2.
Maintained level of Na +/K +-ATPase.
Protective regulatory mechanisms alter molecular expression and function of liver-specific transporters during liver regeneration. Thus, expression of an essential gene such as Na +/K +-ATPase at the basolateral plasma membrane is maintained, whereas there is a downregulation in the expression of absorptive mechanisms for potentially toxic substances such as bile salts under these conditions. In addition, there is continued or increased expression of P-glycoproteins, including Bsep, and Mrp2 at the canalicular membrane that would facilitate the secretion of potentially hepatotoxic bile salts.
Reference-
http://www.medscape.com/viewarticle/410850_4
Regards,
Amol

Dear Bhawna,
Generally, focus on improving bioavailability that can be achieved by inhibiting efllux transporter(which are taking drug out of cells so if we inhibit them drug will remain in cell for some more time). There are some strategies to inhibit efflux transporter:
(a) by a blocking of drug binding sites either competitively or allosterically,
(b) by interfering with ATP hydrolysis and
(c) by altering the integrity of cell membrane lipids.
Different types of inhibitors can be used for this purpose:
e.g. ketoconazol, atorvastatin.
1) The oral bioavailability of tacrolimus was doubled when coadministrating the inhibitor ketoconazole and
2) The bioavailability of digoxin was improved in vivo, when coadministrating atorvastatin.
Hope you got from explanation. For further details refer following article:
M. Werle. Polymeric and Low Molecular Mass Efflux Pump Inhibitors for Oral Drug Delivery. Journal of Pharmaceutical Sciences 97 (2008) 60–70.
Regards,
Amol

Dear Murthy Sir,
1.Drug transporters are both type saturable( mostly drug transport from apical to basal. e.g. The apical-to-basal
transport of ziduvudine is saturable and inhibited by 2,4-dichlorophenoxyacetate and benzylpenicillin) as well as unsaturable (OATs in brain and CSF).
2. Yes, we can use drug transporters for targetting by chemical modification of new chemical entity.
3. Yes, in some case, e.g. P-gp and MRP1 present in brain- csf region in which MRP1 transport is directed towards blood side (by inactivation of this after drug entrance in brain) and P-gp has oppposite direction transport and it accumulate drug substance to CSF (by activation of this transpoter). They may also play some role in maintaining homeostasis in brain.

References for details-
1) Elizabeth C.M. de Lange. Potential role of ABC transporters as a detoxification system at the blood–CSF barrier. Advanced Drug Delivery Reviews 56 (2004) 1793– 1809.
2) N. Strazielle, J.F. G.Egea. Factors affecting delivery of antiviral drugs to the brain. Rev. Med. Virol. 15 (2005) 105–133.

Dear Shilpa,
There are carrier mediated transport in case of nanoparticles,liposomes or nanorobots. They take(transport) the drug to perticular site by different mechanisms (carrier mediated/targeted drug delivery). Drug transporters which mentioned in my presentation are proteins or gene family members present on the surface of cell membrane which help to take in (influx) or out(efflux) of the cell by active or passive transport system.

Say for example- if drug A should reach to perticular cell present in brain, formulate that drug by nanotechnology then one can bind that drug with some specific substance say B [which has affinity towards some protein(transporter) present on that cell membrane in brain region] or design that drug (during drug development) so that, it can reach easily to that perticular site and give effect.

Hope you got the difference.
Regards,
Amol.

Dear Varsha,
There are endocytosis, pinocytosis, exocytosis, ion-pair, pore transport systems other than active and passive.
If one has to take use of different transporters present in the cell surface of body then drug should be modified according to the specificity of perticular transporter protein present at the site where one has to deliver the drug with better pharmacokinetics and pharmacological effects.
Regards,
Amol

Dear Amit,
During drug development, major risk factor is of designing prodrug approach, it can be modified by a known metabolic system of recipient. But this is most of the time neglected that might lead to cytotoxicity or low bioavailability.
Some other factors should be considered such as rational drug approach by understanding the relationship between chemistry and complex biological system.
For details refer,
A.R. Gennaro.Remington:The science and practice of pharmacy. Mack publishing company,Easton, 19th edition,vol.1, pp.52-56.
If you know some other factors please let me know, I feel very happy.
Regards,
Amol

Dear Shobhadeepthi,
Immunoliposomes are generally of 3 types one, liposomes with antibodies, two, liposomes with antibody and some hydrophilic chain, three, liposomes with antibodies on hydrophilic chains. These all type of immunoliposomes mainly used for detection as well as increases interaction and drug delivery with target cell, specially in case of tumors because of specificity of antibodies.

Regards,
Amol

Dear Komal Madam,
Liposomes are as such contain both hydrophilic and lipophilic surfaces so they carry both type of drugs but they are carriers not transporters in exact sense.
Nanosome form π-Conjugated with target molecule (Signal amplification takes place) π-Conjugate polymers used are Polythiophene, Poly(phenyleneethylene)and Polydiacetylene. This can be used for detection of bacteria such as E. coli, protein-protein interaction and Food Transmutation etc.

Reference for details related to nanosomes:
Dong June Ahn. Fluorogenic Polydiacetylene Nanosomes: Application to Label-Free Nanobio Sensors,Korea University,April 17-19, 2008.

Regards,
Amol

Dear Hemangi,
Transporters are exactly carriers present on the surface of cell (cell membrane)for drug or related substances to get inside the cell as well as to send out from the cell like a gate keeper (like Na- K channel for transport of Na- and K-ion inside and outside the cell). ABC and SLC are the transporter gene families in which many proteins and gene are classified under these families. They have perticular binding site to which some drugs are act as substrate and inhibitors. Depend upon their nature, we can design better drug candidate during drug development process so that, it should give better pharmacokinetic and pharmacological properties.
Hope you got the overall concept of transporters.
For further details you can read any article given in references that will give you better picture.
Regards,
Amol

Dear Jithan Sir,
On the lacalization of transporters various pharmacokinetics and pharmacological properties of drug going to affect. For details check Slide no. 10 in my presentation in which table showing lacation of transporter and related parameter of the drug affected.
Thanks for the query.
Regards,
Amol

Dear One,
These all transporter gene contain certain transporter proteins which are responsible for the transport of different substances in and outside of the cell. During drug development process these substrates and inducers are identified by using different in silico screening methods and invivo techniques, which involves binding sites specificities, mechanism of transport, ATPase activity etc parameters to be considered. and because of overlapping of binding sites and multiple binding sites some drug can act as substrates as well as inhibitors. Mainly it is based upon the structural orientation of the compound and receptor.
Hope you got satisfactory answer. still any doubt/s you are welcome.
Regards,
Amol

Dear Sirisha Madam,
Thanks for your words
As you said main difference between active and passive SLC is energy requirement only.
Thanks for your comments and query. All the best.
Regards,
Amol