Renal clearance mechanisms

Dent et al. have tested the effect of ingestion of cystine, cysteine, or methionine on the blood level and mine output of cystine, using microbiological and polarographic methods their findings are considered to confirm the renal mechanism producing cystinuria. Only the administration of cysteine can raise the cystine level in the blood and its output in the urine, both in normal subjects and in cystinuric patients cystine clearances in the latter are 20-30 times more important than in the normal subject (D18, D19). 

Fusidic acid is adequately absorbed from the gastrointestinal tract, but has also been used topically. It has the important property of good tissue penetration, including entry into bones and joints, but does not reach the cerebrospinal fluid. Elimination of fusidic acid is primarily by non-renal mechanisms, and a proportion is metabolized to several breakdown products detectable in bile. Systemic clearance is increased by hypoalbuminemia, reduced by severe cholestasis, and is unchanged in renal insufficiency (3). 

The study of the mechanism of urinary excretion of amylase and the amylase clearance has been the subject of many studies in recent years. Levitt et. al (79) studied the renal clearance of amylase in renal insufficiency, acute pancreatitis and macro-amylasemia. In acute pancreatitis, the kidney cleared amylase at a markedly increased rate. The ratio of the amylase clearance rate to the creatinine clearance rate (Cgm/Ccr) averaged 3 times normal early in the course of acute pancreatitis, and this elevation could persist after the serum amylase returned to normal. Comparison of an lase clearance to creatinine clearance was to minimize irrelevant changes due to variation in renal function. The increased clearance of amylase makes the urinary amylase a more sensitive indicator of pancreatitis. 

CF patients have larger volumes of distribution of many antibiotics due to an increased ratio of lean body mass to total body mass and lower fat stores. CF patients also have an enhanced total body clearance, although the exact mechanism has not been determined. Increased renal clearance, increased glomerular filtration rate, decreased protein binding, increased tubular secretion, decreased tubular reabsorption, extrarenal elimination, and increased metabolism have all been proposed as possible reasons for the increased clearance. 

Probenecid is a uricosuric agent that blocks the tubular reabsorption of uric acid, increasing its excretion. Because of its mechanism of action, probenecid is contraindicated in patients with a history of uric acid stones or nephropathy. Probenecid loses its effectiveness as renal function declines and should be avoided when the creatinine clearance is 50 mL/minute or less. Its uricosuric effect is counteracted by low aspirin doses, which many patients receive for prophylaxis of coronary heart disease. 

The answer is b. (Hardman, pp 816-818.) Digoxin levels rise with concomitant administration of diltiazem by an unknown mechanism that reduces renal clearance... 

Assuming the capsular pressures opposing the movement of water out of the blood and into the top of the nephron are constant, the net filtration pressure is due largely to the blood pressure. Any fall in blood pressure can have a dramatic effect on the efficiency of filtration and therefore clearance of waste materials. So important is the pressure within the renal vasculature that the kidney is critical in regulating systemic blood pressure via the renin-angiotensin-aldosterone (RAA) axis, a physiological process which relies on transport mechanisms within the renal tubules. 

Rather than looking at a metabolic pathway, similar models for the control of the mechanism of clearance by lipophilicity are demonstrated by considering drugs in general. Figure 5.7 illustrates free drug renal and metabolic clearance for a series of neutral compounds drawn from the literature [4]. 

For hydrophilic drugs (log D7 4 below 0) renal clearance is the predominant mechanism. For drugs with log D74 values above 0, renal clearance decreases with lipophilicity. In contrast to renal clearance, metabolic clearance increases with in-... 

Due to the metabolic stability, low molecular weight and absence of ionization at physiological pH, fluconazole has to rely on renal clearance as its major clearance mechanism. The compound has a log P or D7 4 value of 0.5, which means following filtration at the glomerulus a substantial proportion (80 %) of the compound in the filtrate will undergo tubular reabsorption. The resultant low rate of renal clearance gives fluconazole a 30-h half-life in man and is consequently suitable for once-a-day administration. 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Fifth, there are often additional clearance mechanisms for protein medicines which are more important than the renal and hepatic routes we have been considering. Two examples will illustrate this. 

By 1 year of age, glomerular filtration rate and renal tubular mechanisms for secretion have reached adult levels however, fluid intake may be greater in children. Thus, lithium has a shorter half-life and more rapid renal clearance in children as compared with adults (40). 

About a third of an administered dose of rocuronium is excreted in the urine, the rest being taken up by the liver and excreted unchanged in the bile. Its elimination half-life is just under 100 minutes (Table 6.4). Unlike other aminosteroid relaxants, only very small amounts of the metabolite 17-desacetyl rocuronium have been found in plasma. The clearance of rocuronium is reduced in patients with significant renal and hepatic disease, with a possible prolongation of effect. The same mechanisms are responsible for prolongation of the block in the elderly. 

Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dosage must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the rate-corrected QT interval (QTC) and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 bpm and hypokalemia are relative contraindications to its use. 

Lithium Mechanism of action uncertain suppresses inositol signaling and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase No significant antagonistic actions on autonomic nervous system receptors or specific CNS receptors no sedative effects Bipolar affective disorder-prophylactic use can prevent mood swings between mania and depression Oral absorption, renal elimination half-life 20 h. narrow therapeutic window (monitor blood levels) Toxicity Tremor, edema, hypothyroidism, renal dysfunction, dysrhythmias pregnancy category D Interactions Clearance decreased by thiazides and some NSAIDs... 

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