Renal drug transporters

Bendayan R. Renal drug transport A review. Pharmacotherapy 1996 16 971-985. 

The probable reason for the interaction is that levofloxacin, ofloxacin and to a lesser extent ciprofloxacin, inhibit the secretion of unchanged procainamide by the kidney tubules via renal drug transporters. Levofloxacin also appears to inhibit the secretion ofV-acetylprocainamide. 

Fig. 9.1 Schematic diagram depicting drug transporters and their subcellular localization in the human small intestinal enterocyte (A), hepatocyte (B), and renal tubular cell (C).

Within the OAT family, OAT4 is the only transporter expressed at appreciable levels in both the placenta and in the kidney [54]. The membrane localization of OAT4 within these tissues has not been examined. Steroid sulfates, and ochratoxinA are efficient transport substrates of OAT4, whereas PAH is weakly transported [54]. The functional importance of OAT4 in regulating placental permeability and renal drug elimination is currently unknown. 

It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional capacity may be diminished in the elderly. Thus, compounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult. This age dependence of the rate of renal drug secretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups. 

Metabolites of the cholinesterase inhibitors and in some instances significant amounts of the parent compound are eliminated in the urine. Renal excretion is very important in the clearance of agents such as neostigmine, pyridostigmine, and edrophonium. This is demonstrated by a twofold to threefold increase in elimination half-lives for these drugs in anephric patients. Renal elimination is largely the result of glomerular filtration but probably also involves, at least in the case of quaternary amines, secretion via the renal cationic transport system. 

This chapter is divided into three sections. The first section covers renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15-1, Table 15-1). Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers). The physiology of each segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. Finally, the clinical applications of diuretics are discussed in the third section. 

Lee W, Kim RB. Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol. 2004 44 137-166. 

Intestinal absorption of beta-lactams occurs at least in part by an active mechanism involving a dipeptide carrier, and this pathway can result in interactions with dipeptides and tripeptides (196,197), which reduce the rate of absorption of the beta-lactams. In particular, angiotensin-converting enzyme (ACE) inhibitors, which have an oligopeptide structure, are absorbed by the same carrier (198) and interact with beta-lactams in isolated rat intestine (199). However, there might be a second site of interaction between ACE inhibitors and beta-lactams. Both groups of substances are excreted by the renal anionic transport system, and concomitant administration of both drugs sometimes results in pronounced inhibition of the elimination of beta-lactams (200). In the case of cefalexin, it may not lead to toxic effects. However, when more toxic beta-lactams are used, the possibility of this interaction has to be kept in mind. 

Van Crugten JT, Sallustio BC, Nation RL, Somogyi A. Renal tubular transport of morphine, morphine-6-glucuronide, and mor-phine-3-glucuronide in the isolated perfused rat kidney. Drug Metab Disp 1991 19 1087-1092. 

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