Renal elimination, degree

Animal studies indicating that the drug candidate is primarily eliminated renally and/or physicochemical characteristics making a renal elimination likely are flags suggesting the need to profile candidate drug pharmacokinetics in elderly - since some degree of renal impairment is often observed in this population. 

Administering the correct dose to a patient with renal disease must therefore take into account both the extent to which the drug normally relies on renal elimination, and the degree of renal impairment the most convenient and useful guide to the latter is the creatinine clearance. These issues are now discussed. 

Prototypical agent amitriptyline Inhibits norepinephrine and serotonin reuptake Hepatic metabolism with renal elimination High anticholinergic and antihistamine effects imipramine has high orthostasis profile 2nd degree amines (nortriptyline, desipramine) and doxepin have moderate anticholinergic effects... 

Most renally eliminated moxifloxacin exhibits the largest degree of non-renal elimination (i.e., biliary secretion)... 

The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 min on Day 1 of each 21-day cycle. Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70-90% of the dose recovered unchanged within the first 24 h following administration. Pemetrexed has a steady-state volume of distribution of 16.1 L. Pemetrexed is highly bound (approximately 81%) to plasma proteins. Binding is not affected by the degree of renal impairment. Plasma... 

Fig. 9 Plot of kanamycin elimination half-life versus serum creatinine concentration in patients with varying degrees of (stable) renal failure.

There are pharmacokinetic differences among /1-blockers in first-pass metabolism, serum half-lives, degree of lipophilicity, and route of elimination. Propranolol and metoprolol undergo extensive first-pass metabolism. Atenolol and nadolol have relatively long half-lives and are excreted renally the dosage may need to be reduced in patients with moderate to severe renal insufficiency. Even though the half-lives of the other /J-blockers are much shorter, once-daily administration still may be effective. /J-Blockers vary in their lipophilic properties and thus CNS penetration. 

Altered renal filtration, secretion, and/or absorption can have dramatic effects on the pharmacokinetics of a drug. The impact depends on the fraction of drug normally eliminated unchanged by the kidney and on the degree of renal insufficiency. 

Use in patients with impaired renal function - Perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when Ccr drops below 30 mL/min. In patients with Ccr less than 30 mL/min, safety and efficacy have not been established. For patients with lesser degrees of impairment (Ccr more than 30 mL/min), the initial dosage should be 2 mg/day, and dosage should not exceed 8 mg/day because of limited clinical experience. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function. 

Metabolism/Excretion Zalcitabine is phosphorylated intracellularly to zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. Concentrations of zalcitabine triphosphate are too low for quantitation. Metabolism has not been fully evaluated. Zalcitabine does not appear to undergo a significant degree of metabolism by the liver. Renal excretion appears to be the primary route of elimination, and accounted for approximately 70% of an orally administered dose within 24 hours after dosing. The mean elimination half-life is 2 hours. Total body clearance following an IV dose averages 285 mL/min. Less than 10% of a dose... 

Pharmacokinetics According to the product label, the pharmacokinetics of eptihbatide are linear and dose proportional. Plasma elimination half-life is approximately 2.5 hours. The extent of eptihbatide binding to human plasma protein is about 25% its mean volume of distribution is 185mPkg. Clearance in patients with coronary artery disease is 55-58 ml/kg per hour. Clinical studies have included 2418 patients with serum creatinine between 1.0 and 2.0mg/dl without dose adjustment. No data are available in patients with more severe degrees of renal impairment, but plasma eptihbatide levels are expected to be higher in such patients. Patients in clinical studies were older than the subjects in clinical pharmacology studies, and they had lower total body eptihbatide clearance and higher eptihbatide plasma levels. Men and women showed no important differences in the pharmacokinetics of eptihbatide. 

Most ACE inhibitors are eliminated primarily via the kidney. However, fosinoprilat is excreted about equally in the bile and urine (148). Biliary excretion can compensate for compromised renal function, and thus blood levels of fosinoprilat remain relatively constant in patients with varying degrees of renal impairment (150). 

There are wide variations in the clinical manifestations and degrees of expression of toxicity as patients are exposed to Al. In renal disease Al accumulation in tissues and its resulting toxicity is mainly due to poor elimination, since the kidney normally excretes the metal. There is no simple relationship between the amount of Al to which the patient is exposed and the occurrence of the clinical manifestations of the disease apparently there is considerable interindividual difference in sensibility since the symptoms developed in some patients but not in other equally exposed patients. Some of the variations in the clinical features in Al toxicity in the past most likely occurred because of differences in both the rapidity and magnitude of Al loading. Therefore, the manifestations of Al toxicity that are encountered vary substantially, with major differences arising due to different sources and varying intensity of the Al burden. 

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