Renal secretion clearance

The marker remains in the plasma without binding to proteins, and the filtrate is neither reabsorbed nor secreted by the renal tubule. Clearance rate of the marker from plasma equals the glomerular filtration rate (GFR). The polysaccharide, inulin, typifies this class of markers. 

The renal drug clearance is influenced by alterations in glomerular filtration rate and tubular reabsorption or secretion rate. 

Figure 8 Effect of probenecid on the plasma concentration of famotidine in healthy volunteers. Plasma concentration of famotidine was determined in healthy subjects treated with or without probenecid. The renal and tubular secretion clearances were decreased by the probenecid treatment (CLrenai 279 vs. 107 mL/min and CLsec 196 vs. 22 mL/min). Source (A) from Ref. 348 and (B) from Ref. 337.

Benzylpenicillin disappears from the blood very rapidly (the elimination half-life is 30 minute in the adult), and 60-90% of dose is excreted in the urine (350). The renal clearance is approximately equal to the blood flow rate, indicating a high secretion clearance (350). Probenecid and phenylbutazone reduced its renal clearance to 60%, while sulfinpyrazone reduced it to 40% of the control value (351). In rat kidney, Oat3 has been suggested to be responsible for the uptake of benzylpenicillin (53). As discussed above, inhibition of uptake process mediated by OAT3 is likely mechanics underlying this interaction. 

The renal drug clearance, as the major excretion route, is influenced to different extents by urine flow, urine pH and plasma protein binding. The extent of sensitivity to these parameters depends on the nature of compounds and mechanisms involved in its renal elimination (e.g. glumerular filtration, active secretion, passive re-absorption). Thus, interindividual variation in these parameters together with renal function determines the overall renal clearance, The urine flow is sensitive to individual fluid intake and administration of diuretic drugs. Interindividual differences in urine pH are mainly related to differences in diet and physical activity. 

A number of drugs are known to inhibit the renal secretion of certain other drugs, resulting in decreased clearance of the latter. Examples of drugs decreasing the renal clearance of other drugs include probenecid, salicylates, sulfinpyrazone, phenylbutazone, and thiazide diuretics. As mentioned previously, the inhibition of penicillin secretion by probenecid due to competition between the two for renal tubule carriers is used therapeutically to increase penicillin blood levels. 

Possible mechanisms responsible for this stereoselective renal clearance of pindolol appear to be stereoselective renal metabolism or stereoselective renal secretion (stereoselective binding to plasma proteins was not observed). Recently, Somogyi et al. investigated the effect of coadministration of dmetidine on the renal clearance of the two enantiomers of pindolol (58). Cimetidine significantly reduced the renal clearance of both enantiomers, but reduced the renal clearance of the R enantiomer by a greater extent than the S enantiomer. These data are consistent with the stereoselective renal elimination mechanism for pindolol, with the S enantiomer being preferentially cleared. 

Although diastereoisomers, both quinine and quinidine, have similar physical properties (Fig. 18). In clinical studies, the renal clearance of quinidine was fourfold greater than that of quinine (57). No stereoselective differences in plasma protein binding were observed. The renal filtration and passive reabsorption of these two diastereoisomers should be similar since the compounds have similar octanol-water partition coefficients and pKa values (57). Therefore, stereoselective active renal secretion may be the mechanism responsible for the observed differences in the renal clearances of quinine and quinidine. 

Further clinical examples of potential stereoselective renal secretion of organic cations have been recently reported. A major metabolite of verapamil (D-617) is actively secreted by the kidney (59). Upon coadministration of dmetidine, the renal clearance of the S-D-617 isomer was significantly decreased, whereas the clearance of the R-D-617 metabolite was unaffected by dmetidine administration (59). Stereoselective renal secretion was suggested as the mechanism of this effect. However, it is not known if this metabolite is actually secreted by the organic cation transport system. The renal clearance of unbound S(+) disopyramide was... 

Oxalate is excreted primarily by the kidney. Oxalate is freely filtered at the glomerulus, where its concentration is normally 1 5 pM. One of the few physiologic functions of oxalate occurs in the proximal tubule where it plays a role in transcellular reabsorption of chloride (mainly present as sodium chloride). Cl entry across the apical membrane is mediated by Cl /oxalate exchange (oxalate is recycled from the tubular lumen to the cell by oxalate/ sulfate exchange, in parallel with Na /sulfate cotransport) [4]. Early studies of renal oxalate clearance using radio-labeled oxalate showed secretion in almost all subjects studied. More recent studies using direct measurement of serum and urine... 

Saturated renal excretion For example, dicloxa-cillin demonstrates saturable active renal secretion showing decreased renal clearance with increased dose. 

Clearance is mainly hepatic or renal hepatic clearance is quantified by treating the liver as a virtual enzyme. Renal clearance is divided between glomerular filtration, active secretion, and reabsorption. 

Alterations in one or more of the three renal processes (filtration, secretion, or reabsorption) secondary to reductions in functional nephron mass may have a dramatic effect on the pharmacokinetics of a drug. A reduction in glomerular filtration rate results in a decrease in renal drug clearance. For drugs that are extensively renally secreted (CLr >300 mL/min), the loss of filtration clearance (up to 120 mL/min) will have less of an impact than for those primarily dependent on GFR. 

The use of these calculations is limited in toxicology (Lefebvre et al. 2008) but occasionally used when comparing the clearance of a xenobiotic that also affects electrolyte renal secretion and excretion rates. 

Severe somnolence and lethargy may occur with combinations of zidovudine and acyclovir. Concomitant cyclosporine enhances nephrotoxicity. Probenecid decreases acyclovir renal clearance and prolongs the plasma t of elimination. Acyclovir may decrease the rerml clearance of other drugs eliminated by active renal secretion (e.g., methotrexate. ... 

The GFR can be estimated by clearance measurements of endogenous or exogenous small molecules (urea, creatinine, 2-MPT, inulin, cystatin C, iohexol, or iodixanol). An ideal marker of GFR should be primarily excreted by the kidneys, freely filtered by the glomerulus, and neither secreted nor reabsorbed by the tubule. It should also be supplied to the plasma at a constant rate and exhibit no or minimal protein binding. If these criteria are met, such as for inulin, the GFR is equivalent to the renal/urinary clearance of the substance, as defined earlier in this chapter. 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Two types of diuretics are used for volume management in HF thiazides and loop diuretics. Thiazide diuretics such as hydrochlorothiazide, chlorthalidone, and metolazone block sodium and chloride reabsorption in the distal convoluted tubule. Thiazides are weaker than loop diuretics in terms of effecting an increase in urine output and therefore are not utilized frequently as monotherapy in HF. They are optimally suited for patients with hypertension who have mild congestion. Additionally, the action of thiazides is limited in patients with renal insufficiency (creatinine clearance less than 30 mL/minute) due to reduced secretion into their site of action. An exception is metolazone, which retains its potent action in patients with renal dysfunction. Metolazone is often used in combination with loop diuretics when patients exhibit diuretic resistance, defined as edema unresponsive to loop diuretics alone. 

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