By Guofeng, Ed. You
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Extra info for Drug Transporters: Molecular Characterization and Role in Drug Disposition (Wiley Series in Drug Discovery and Development)
1. 2. 3. 4. 5. 1. 2. 3. 6. 1. 2. 3. 4. 7. 1. 2. 3. 8. Conclusions References Drug Transporters: Molecular Characterization and Role in Drug Disposition, Edited by Guofeng You and Marilyn E. Morris Copyright C 2007 John Wiley & Sons, Inc. 1. INTRODUCTION Renal elimination, including both passive glomerular ﬁltration and active tubular secretion, is a major route of clearance for many drugs and drug metabolites. Active secretion of drugs by the kidney takes place primarily in the renal proximal tubule, where drug transporters facilitate the ﬂux of drug molecules from the blood to the tubular lumen for excretion.
65 Further studies investigated the role of Oct1 in the development of metformin-induced lactic acidosis, a leading toxicity from this drug. 66 Taken together, these results suggest that Oct1-mediated metformin transport is a limiting step in metformin uptake into liver, and that the lactic acidosis induced by metformin is related to the availability of the drug to this target organ. 2. 67 However, unlike the Oct1 –/– mice, pharmacokinetics of intravenous [14 C]TEA were quite similar in Oct2 –/– mice and wild-type mice, with the exception of a slight decrease in distribution of TEA into brain in Oct2-deﬁcient mice.
Although the effect of muscarinic receptor stimulation on OCT2 activity is partially explained by its effects on intracellular Ca2+ , 22 ORGANIC CATION TRANSPORTERS additional studies have shown that the majority of this effect is due to activation of phospatidylinositol 3-kinase (PI3K), as inhibition of PI3K almost completely prevents the inhibitory effect of carbachol on OCT2-mediated transport. These studies suggest that PKA, PI3K, and the Ca2+ –calmodulin complex are endogenous regulators of OCT2; however, in contrast to the effect of protein kinases on OCT1, the inhibition of transport activity is not explained by effects on substrate-binding afﬁnity.
Drug Transporters: Molecular Characterization and Role in Drug Disposition (Wiley Series in Drug Discovery and Development) by Guofeng, Ed. You