Drug transport
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Transcript of Drug transport
Learning Outcome :
Importance of drug transporter
Types of drug transporter
Function and mechanism of P-glycoprotein
Clinical importance of P-glycoprotein
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 / bidirectionaltransporter
Utilize energy from ATP Electrochemical gradient / facilitated diffusion
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
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”