Kidney tubular secretion

In 6 healthy subjects probenecid (1 g given orally 2 hours before meropenem and 500 mg given orally 1.5 hours after meropenem) increased the AUC of meropenem 500 mg by 43%. Another study in 6 healthy subjects found that probenecid (1.5 g in divided doses the day before and 500 mg one hour before meropenem) increased the AUC of meropenem 1 g by up to 55% and increased its half-life by 33% (from 0.98 to 1.3 hours). In both studies the serum levels of meropenem were modestly increased. This is possibly because meropenem and probenecid compete for active kidney tubular secretion. The manufacturers say that because the potency and duration of meropenem are adequate without probenecid, they do not recommend concurrent use. ... 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

Several hydrophilic, anionic technetium complexes can be used to perform imaging studies of the kidneys. Tc-Mertiatide (Fig. 5a) is rapidly excreted by active tubular secretion, the rate of which is a measure of kidney function. Tc-succimer (Fig. 5b), on the other hand, accumulates in kidney tissue thus providing an image of kidney morphology. 

Technetium-99m mertiatide (A/-[Ai-[A/-[(benzoylthio)acetyl]glycyl]glycine) is a renal imaging agent. It is excreted by the kidneys via active tubular secretion and glomerular filtration. The kit vial is reconstituted by using 740—3700 MBq (20—100 mCi) of Tc pertechnetate and boiling for 10 minutes. 

Potassium balance is also primarily regulated by the kidney via the distal tubular cells. Reduction in nephron mass decreases tubular secretion of potassium, leading to hyperkalemia. Hyperkalemia is estimated to affect more than 50% of patients with stage 5 CKD.28... 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

The rate of total body clearance accounted for by the kidney. Its magnitude is determined by the net effects of glomerular filtration, tubular secretion and reabsorption, renal blood flow, and protein binding. 

Radiopharmaceuticals are the preferred agents for the assessment of function, as opposed to structure. Renal imaging agents are classic examples in that sense, since they allow the monitoring of the imaging of glomerular filtration and tubular secretion functions of the kidneys. Currently there are two agents available one is Tc-DTPA of unknown structure, and the other one is the... 

It does not inhibit cytochrome P450. Gatifloxacin is excreted as unchanged drug primarily by the kidney. Gatifloxacin undergoes glomerular filtration and tubular secretion. 

Probenecid Coadministration of probenecid results in an approximate 2-fold increase in exposure to oseltamivir carboxylate because of a decrease in active anionic tubular secretion in the kidney. 

Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Entecavir undergoes both glomerular filtration and net tubular secretion. 

Drugs affected by renal function impairment Because entecavir primarily is eliminated by the kidneys, coadministration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. 

Renal development is also immature in both the premature and the full-term baby. At birth overall renal function is approximately 20% of the adult value, but increases rapidly up to around one year of age when it is usually the same as that of an adult (when adjusted for body size). Glomerular filtration rate in particular may increase four-fold over the first week of life. As renal blood flow, glomerular filtration rate and tubular secretion of drugs are all low in the neonate, drugs cleared by the kidney need to be given in reduced dose - particularly if the drug has a narrow therapeutic window , and the potential to produce toxicity if Cp rises too greatly. 

Natiuretic response to diuretics including fruse-mide and bumetanide is reduced as a result of decreased renal tubular secretion of diuretic Thus, age-related changes in renal tubular function may influence not only pharmacokinetics but also drug action on the kidney (pharmacodynamics). 

Any drug known to be largely excreted by the kidney that has a body half-life of less than 2 hours is probably eliminated, at least in part, by tubular secretion. Some drugs can be secreted and have long half-lives, however, because of extensive passive reabsorption in distal segments of the nephron (see Passive Diffusion, earlier in the chapter). Several pharmacologically active drugs, both anions and cations, known to be secreted are listed in Table 4.5. 

Penicillin G is excreted by the kidneys, with 90% of renal elimination occurring via tubular secretion and 10% by glomerular filtration. Probenecid blocks tubular secretion and has been used to increase the serum concentration and prolong the half-life of penicillin G and other penicillins. Additional pharmacokinetic information can be found in Table 45.1. 

Cidofovir has extremely low oral bioavailability and so must be administered intravenously. Although the plasma elimination half-life averages 2.6 hours, the diphosphate form of the drug is retained within host cells and has an intracellular half life of 17 to 65 hours. A phosphocholine metabolite has a half-life of approximately 87 hours and may serve as an intracellular reservoir of the drug. Cidofovir is not significantly metabolized and is excreted unchanged by the kidney. Glomerular filtration and probenecid-sensitive tubular secretion are responsible for cidofovir elimination. 

The plasma elimination half-life for penciclovir is 2 to 3 hours however, the intracellular half-life of penciclovir triphosphate is 7 to 20 hours in infected cells. Most penciclovir is eliminated unchanged by the kidney via glomerular hltration and active tubular secretion. The plasma half-life is increased in individuals with renal insufficiency. 

Effect on kidney In low doses, aspirin inhibits the tubular secretion of uric acid and... 

Most of the drug is excreted unchanged by the kidney by tubular secretion and glomerular filtration.9-Carboxymethoxymethylguanine is the only significant metabolite of acyclovir recovered from the urine. 

The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2-3 hours) and is nearly as complete as with intravenous administration. The duration of effect for furosemide is usually 2-3 hours and that of torsemide is 4-6 hours. Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known if they have any diuretic activity. Torsemide has at least one active metabolite with a half-life considerably longer than that of the parent compound. 

Penicillin is rapidly excreted by the kidneys small amounts are excreted by other routes. About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion. The normal half-life of penicillin G is approximately 30 minutes in renal failure, it may be as long as 10 hours. Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour. For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one fourth to one third the normal dose being administered if creatinine clearance is 10 mL/min or less (Table 43-1). 

If the rate of elimination decreases in Scheme 7.2, then what happens to clearance Clearance is unchanged. For each 4.0-second pass, the liver clears 50 mL (CLh = 12.5 mL/s) out of the total 100 mL of blood that flows through the organ. Literally, 50% of the blood volume is cleared, so the actual impact is a decrease in Cp by 50%. While clearance is constant, the effect of clearance on Cp varies with Cp. Clearance depends on the action of metabolic enzymes on the drug and, at very high drug concentrations, the enzymes can become saturated with substrate. Under these conditions, which are rare, clearance is not constant. Therapeutic concentrations of modem drugs are normally well below the concentrations required to saturate liver enzymes. The tubular secretion and reabsorption processes in the kidneys can also be saturated and affect renal clearance. As with hepatic clearance, variable renal clearance is rare. 

As glomerular filtration has an approximate molecular size limit of 20-30 kDa, mAbs do not undergo filtration in the kidneys due to their relatively large size. The situation is different, however, for low molecular-mass antibody fragments, which can be filtered. Tubular secretion has not been reported to occur to any significant extent for mAbs, and peptides/small proteins are readily reabsorbed in the proximal or distal tubule of the nephron (potentially also mediated by the neonatal Fc receptor, Fc-Rn), or are even metabolized. Thus, renal elimination in total is uncommon or low for mAbs. Biliary excretion of mAbs has been reported only for IgA molecules, and only to a very small extent. Therefore, total clearance (CL) does usually not comprise renal or biliary clearance. 

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