Category Archives: Tedisamil

The kidney: SUMMARY

Renal clearance of drugs is a dynamic process involving filtration, secretion and reabsorption. While seemingly as chaotic as a schoolyard at recess time, these transport mechanisms work in unison to clear potentially toxic drug metabolites. The clinical importance of renal tubular transport systems is not only limited to drug interactions and toxicity. Emerging evidence suggests that the expression of transport proteins or their activity can … Continue reading

The kidney: CLINICAL SIGNIFICANCE OF KIDNEY P-GP

MDR1-type P-gp has been shown to transport a variety of drugs including vinca alkaloids, cyclosporin, colchicine, tacrolimus, anthracyclines, etoposide, verapamil, diltiazem, nifedipine, propafenone, digoxin, chloroquine and protease inhibitors, including saquinavir, ritonavir and nelfinavir. There is still debate about dideoxynucleosides such as zidovudine and dideoxyinosine.

The kidney: TRANSPORT PROTEINS AND HUMAN IMMUNODEFICIENCY VIRUS MEDICINE

The greatest challenge for predicting HIV medication failures, second to drug efflux mechanisms or interactions, is the relative lack of specificity of transport systems for HIV drugs. There is an increasing pool of data to suggest that nucleoside analogs are not only transported by nucleoside transporters, but also by OCTs. MRP4, for example, has been linked to the efflux of nucleoside monophospate analogs, and, in … Continue reading

The kidney: CLINICAL SIGNIFICANCE OF RENAL TUBULAR SECRETORY MECHANISMS(2)

Tables 4 and 5 provide a summary of the major cloned human renal tubular transport systems grouped as having either anionic or cationic substrates. Knowing the basic properties of these transport systems may be useful in predicting potential drug interactions. Methotrexate and nonsteroidal anti-inflammatory (NSAIDs) are organic anions believed to be transported by OAT1. Animal models suggest that OATs are involved in the methotrexate-NSAIDs interaction. Trimethoprim, … Continue reading

The kidney: CLINICAL SIGNIFICANCE OF RENAL TUBULAR SECRETORY MECHANISMS(1)

Drugs can affect the renal excretion of other drugs leading to pharmacokinetic drug interactions. The mechanisms for drug-induced alterations in renal drug clearance are not fully known. One mechanism involves the alteration of urinary pH. Another mechanism depends on the tubular transport mechanisms. If two drugs are eliminated through the same tubular secretion protein, then one or both drugs may have reduced excretion, increased serum … Continue reading

The kidney: UNIQUE TRANSPORTERS EXIST FOR PEPTIDES, CONJUGATES, HYDROPHOBIC DRUGS AND NUCLEOSIDES(2)

Human prostaglandin transporter (hPGT) appears to be able to mediate the transport of prostaglandins, including PGE1, PGE2, PGD2 and PGF2a. PGT is not limited to the renal tubules and can be found in most tissues. The exact role of PGT in prostaglandin handling is unknown.

The kidney: UNIQUE TRANSPORTERS EXIST FOR PEPTIDES, CONJUGATES, HYDROPHOBIC DRUGS AND NUCLEOSIDES(1)

Peptide transporters are involved in the electrogenic hydrogen-coupled cotransport of dipeptides and tripeptides. The drive for this comes from an inward hydrogen gradient and a negative transmembrane potential difference. Two homologous PEPTs have been described: PEPT1 and PEPT2, with the latter showing higher affinity for a variety of substrates. PEPTs mediate transport of peptide-like drugs, including beta-lactam antibiotics, angiotensin-converting enzyme (ACE) inhibitors and the dipeptide … Continue reading

The kidney: TRANSPORT MECHANISMS IDENTIFIED WITHIN HUMAN RENAL TUBULAR CELLS(3)

Organic anions are able to enter renal tubular cells from the ECF via the dicarboxylate-organic anion exchanger. This entry of anions is coupled with a sodium-dicarboxylate (a-ketoglutarate [a-KG]) exchanger that moves dicarboxy-lates outwards. The process is driven by an inward sodium gradient established by a sodium-potassium ATPase. Ionic compounds such as para-aminohippurate (PAH) and ben-zylpenicillin are substrates for the organic anion transporter (OAT) systems in … Continue reading

The kidney: TRANSPORT MECHANISMS IDENTIFIED WITHIN HUMAN RENAL TUBULAR CELLS(2)

A summary of most of these models for renal drug handling of organic cations, organic anions, conjugated drugs and hydrophobic agents, including the proteins representing specific transport mechanisms, is presented graphically in Figure 2. The following sections describe these mechanisms in more detail. For easier conceptualization, the transporter proteins described below are grouped by their location at either the basolateral or apical membrane of renal … Continue reading

The kidney: TRANSPORT MECHANISMS IDENTIFIED WITHIN HUMAN RENAL TUBULAR CELLS(1)

The old teaching was that hydrophilic drugs may pass through the tubule and are excreted in the urine, while lipophilic drugs can cross at various places along the membrane and are reabsorbed into the plasma. Data from molecular biology techniques and gene ‘knock-out’ experiments have elucidated information concerning active transport mechanisms and have identified several novel transport proteins for organic cations and anions. There is … Continue reading