Renal clearance influence

Renal clearance of cotinine is much less than the glomerular filtration rate (Benowitz et al. 2008b). Since cotinine is not appreciably protein bound, this indicates extensive tnbnlar reabsorption. Renal clearance of cotinine can be enhanced by np to 50% with extreme urinary acidification. Cotinine excretion is less influenced by urinary pH than nicotine becanse it is less basic and, therefore, is primarily in the unionized form within the physiological pH range. As is the case for nicotine, the rate of excretion of cotinine is influenced by urinary flow rate. Renal excretion of cotinine is a minor route of elimination, averaging about 12% of total clearance. In contrast, 100% of nicotine Ai -oxide and 63% of 3 -hydroxycotinine are excreted unchanged in the urine (Benowitz and Jacob 2001 Park et al. 1993). 

Benowitz N, Lessov-Schlaggar C, Swan G (2008b) Genetic Influences in the Variation in Renal Clearance of Nicotine and Cotinine. Clin Pharmacol Ther 84(2) 243-247 Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S (1997) Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282(1) 7-13... 

In renal failure changes in apparent volume of distribution do occur, and changes in a patient s hydration in particular can influence this, and therefore the renal clearance. However, the main message is that reduced renal function reduces the renal clearance of gentamicin, and this must lead to an increase in dosing interval. 

Orally active agents used in the treatment of ED are more affected by aging and disease processes than are those injected intracavernosally. In addition, alterations in hepatic metabolism and/or renal clearance in the elderly man (see Chapter 6) influence the frequency of appearance of adverse reactions between several coadministered drugs in the treatment of ED. For example, the concomitant use of sildenafil and nitroglycerin is contraindicated by cardiovascular complications. Also, the use of testosterone in the presence of androgen-dependent tumors may promote tumor growth. 

Marked inter-patient variability exists in the pharmacokinetics of intravenous anaesthetics. Factors that can influence drug disposition include the degree of protein binding, the efficiency of the hepatic and renal clearance systems, physiological changes with ageing, disease states, site of operation, body temperature, and drug interactions (premedicants, volatile anaesthetics). 

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. 

There are also other types of drug interactions, including impaired uptake of drugs from the GI tract and altered renal clearance, for example. A summary of mechanisms by which nutrients and drugs can influence each other is shown in... 

Hyperuricaemia and gout from whatever cause (e.g. metabolic, renal disease, neoplasia) depends essentially on two processes, (1) overproduction and (2) underexcretion of urate. Both mechanisms may operate in the same patient but decreased renal clearance contributes to hyperuricaemia in most patients with gout. Drugs may influence these processes as follows ... 

Methotrexate is readily filtered by the kidneys, and renal clearance is influence by both tubular secretion [139, 140, 141, 142] and tubular reabsorption [142]. Intravenous administration of methotrexate 140-350 mg/kg [<6h infusion] results in 70-94% of the dose appearing in the urine over 24 h [143]. In contrast, when methotrexate is administered as a 24-h continuous infusion, 60% of the dose is excreted in the mine during the 24-h infusion [144]. Approximately 10% of the dose is excreted in the urine as 7-hydroxymethotrexate [143,144]. The 7-hydroxy metabohte is important since it may contribute to the renal toxicity of methotrexate [148] and this moiety becomes a significant metabolite when methotrexate doses are 50 mg/kg or greater [145]. Following oral administration of methotrexate a lesser fraction of the dose is recovered in the urine than following intravenous administration [141]. This may reflect the dose-dependent incomplete absorption of methotrexate [141,146,147]. Methotrexate is highly bound to plasma proteins. 

Salicylate and its metabolites are rapidly and almost completely excreted in the urine by glomerular filtration and by renal tubular secretion. Passive reabsorption of salicylate occurs in the distal tubules. Salicylate elimination is saturable and characterized by Michaelis-Menton kinetics where the elimination half-life is dependent on the dose. Since the pRa of salicylic acid is 3, its renal clearance is greatly influenced by changes in urinary pH. Increasing urinary pH can significantly increase the overall salicylate elimination rate via ion trapping. 

The renal clearance of sulfamethoxazole, but not of its metabolite, Nij-acetylsulfamethoxazole, was markedly influenced by urinary pH and urine flow. Pharmacokinetic analysis of percutaneous absorption showed evidence of parallel penetration pathways for methotrexate when it was topically applied to hairless mouse skin. ... 

Weakly acidic and basic drugs can exist in ionized (charged) and nonionized (uncharged) forms, depending on their pKa values and the pH of the medium (eg, blood, urine). Because nonionized forms are capable of reabsorption across tubular membranes, the renal elimination of acids and bases can be influenced by changes in urinary pH. If the renal clearance of a drug does not change when urinary pH increases, then the compound must be a nonelectrolyte. 

Eiermaim, B., Sommer, N., Winne, D., Schumm, R, Maier, U., and Breyer-Pfaff, U., Renal clearance of pyridostigmine in myasthenic patients and volunteers under the influence of ranitidine and pirenzepine, YenoWotica, 23, 1263, 1993. 

Stereoselectivity in renal clearance may arise as a result of either selectivity in protein binding, influencing glomerular filtration and passive reabsorption, or active secretion or reabsorption. Enantioselectivity in renal clearance has been reported for a number of drugs, and in the majority of instances the selectivity is relatively modest, with enantiomeric ratios between 1.0 and 3.0 (Table 4). In the case of the diastereoisomers quinine and quinidine, the diiference is about fourfold, with values of 24.7 and 99 mLmin in man, respectively [128]. 

Hildebrandt R, Moller H, Gundert-Remy U. Influence of tiieophylUne on tiie renal clearance of erytiiromycin. IntJ CUnPharmacol Ther Tcocicol (19S7) 25, 601-4. 

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