Glycoprotein polymorphism

While effects of P-glycoprotein polymorphisms have been reported for intestinal uptake, no such studies exist for effects on blood-brain barrier penetration. If certain polymorphisms were to alter intracerebral concentrations of specific antidepressants, prior knowledge of the patients relevant P-glycoprotein genotypes could prevent the administration of a drug that might never reach therapeutic intracerebral levels despite a normal plasma concentration. 

Roberts RL, Joyce PR, Mulder RT, Begg EJ, Kennedy MA. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J 2002 2 191-196. 

Transferrin (Tf) is a Pj-globulin with a molecular mass of approximately 76 kDa. it is a glycoprotein and is synthesized in the liver. About 20 polymorphic forms of transferrin have been found, it plays a central role in the body s metabolism of iron because it transports iron (2 mol of Fe + per mole of Tf) in the circulation to sites where iron is required, eg, from the gut to the bone marrow and other organs. Approximately 200 billion red blood cells (about 20 mL) are catabolized per day, releasing about 25 mg of iron into the body—most of which will be transported by transferrin. 

Ishikawa, T., Onishi, Y., Hirano, H. et al. (2004). Pharmacogenomics of drug transporters a new approach to functional analysis of the genetic polymorphisms of ABCB1 (P-glycoprotein/MDRl). Biol. Pharm. Bull., 27, 939 48. 

Wu, Z., Nagano, I. and Takahashi, Y. (1998) The detection of Trichinella with polymerase chain reaction (PCR) primers constructed using sequences of random amplified polymorphic DNA (RAPD) or sequences of complementary DNA encoding excretory-secretory (E-S) glycoproteins. Parasitology 117, 173-183. 

Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H. P., Brockmoller, J., Johne, A., Cascorbi, I., Gerlo, T., Roots, I., Eichelbaum, M., Brinkmann, U., Functional polymorphism of the human multidrug resistance gene multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo, Proc. Natl. Acad. Sci. USA 2000, 97, 3473-3478. 

Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y et al. Expression of P-glycoprotein in human placenta relation to genetic polymorphism of the multidrug resistance (MDR)-l gene. J Pharmacol Exp Ther 2001 297(3) 1137-1143. 

Hoffmeyer, S., et al., "Functional Polymorphisms of the Human Multidrug-Resistance Gene Multiple Sequence Variations and Correlation of One Allele with P-Glycoprotein Expression and Activity In Vivo," Proc. Natl. Acad. Sci. U.S.A., 97, 3473-3478 (2000). 

For other efflux transporters such as BCRP (ABCG2), human pharmacokinetic and pharmacodynamic data are currently rare. However, an investigation of the influence of polymorphisms in ABC-transporter genes on the accumulation of nelfinavir in peripheral blood mononuclear cells (PBMCs) revealed no associations between the polymorphisms in the transporters analyzed and the accumulation of nelfinavir in the PBMCs [151], A second study in patients clearly demonstrated an increase in the AUC of the orally and intravenously administered BCRP substrate topotecan when it is given with GF120918, an inhibitor of P-glycoprotein and BCRP [152],... 

Drescher, S., Schaeffeler, E., Hitzl, M., Hofmann, U., Schwab, M., Brinkmann, U., Eichelbaum, M. and Fromm, M.F. (2002) MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. British Journal of Clinical Pharmacology, 53, 526-534. 

Takano, A., Kusuhara, H., Suhara, T., Ieiri, I Morimoto,T., Lee, Y.J., Maeda, J., Ikoma, Y., Ito, H., Suzuki, K. and Sugiyama, Y. (2006) Evaluation of in vivo P-glycoprotein function at the blood-brain barrier among MDR1 gene polymorphisms by using HC-verapamil. Journal of Nuclear Medicine, 47, 1427-1433. 

Kurata, Y., leiri, I., Kimura, M., et al. (2002) Role of human MDRl gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin. Pharmacol. Ther. 72, 209-219. 

Meissner, K., Jedlitschky, G., Meyer zu Schwabedissen, H., et al. (2004) Modulation of multidrug resistance P-glycoprotein 1 (ABCBl) expression in human heart by hereditary polymorphisms. Pharmacogenetics. 14, 381-385. 

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