Drug/metabolite transporters

The mechanism by which PfCRT confers resistance to chloroquine is still under discussion [75], The first aspect concerns the nature of the protein whether PfCRT, postulated to possess ten transmembrane helices, is considered as a member of the drug-metabolite transporter family of proteins [55, 76-78], Some authors discuss about the channel nature of the protein [79, 80], It has been suggested that the change of the charged lysine to uncharged threonine affects the electrostatic interaction with the diprotonated CQ [81]. In the mutated forms, the absence of electrostatic interactions allows the drug to cross the channel (Fig. 6). This results in the efflux of the drug out of the DV [81]. Note here that the reduced accumulation can be partially reversed by verapamil, a lipophilic compound (Fig. 5). 

The smahest known secondary active transporters belong to the SMR family within the drug metabolite transporter (DMT) superfamiiy (23). 

Jack DL, Yang NM, Saier MH Jr. The drug/metabolite transporter superfamily. Eur. J. Biochem. 2001 268 3620-3639. 

Excluding the MFS, the three largest superfamilies of secondary transporters include the Resistance/ Nodulation/Division (RND) exporters (exclusively export carriers Tseng et al. 1999 Dehnar et al. 2014), the Drug/Metabolite Transporters (DMT) (both uptake and efflux systems Jack et al. 2001 Yen et al. 2010), and the Multidrug/Oligosaccharide/Polysaccharide (MOP) porters (exclusively efflux pumps Hvorup et al. 2003b). These three superfamilies will be examined sequentially in this section. 

Regardless of the type of chemical reaction used, biotransformation also helps in metabolite excretion from the body by creating a more polar compound.18,53 60 After one or more of the reactions just described occurs, the remaining drug metabolite usually has a greater tendency to be ionized in the body s fluids. The ionized metabolite is more water soluble, thus becoming transported more easily in the bloodstream to the kidneys. Upon reaching the kidneys, the polar metabolite can be excreted from the body in the urine. The contribution of biotransformation toward renal excretion is discussed in a later section. 

Robertson EE, Rankin GO (2006) Human renal organic anion transporters characteristics and contributions to drug and drug metabolite excretion. Pharmacol Ther 109(3) 399-412... 

Although this review focuses specifically on metabolism, the increasing knowledge of the intimate connections between metabolism and transport must be mentioned. There are many situations in which the interaction of transporters with drug metabolites has been explored and has led to the hypothesis that CYP, and other enzymes and transporters, work in concert to keep xenobiotics from crossing the intestinal epithelium.44 17 Cases in which there seems to be coordinate activity to preferentially export drug metabolites have been found in Caco-2 cells and in vivo with esterase enzymes and with CYP enzymes. 

A. Compounds known to be secreted by the renal organic acid (anion) transport system. Endogenous compounds Drug metabolites Drugs... 

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