Renal insufficiency drug metabolism

Oral bisphosphonates are poorly absorbed (less than 5%). Taking them in the presence of food or calcium supplementation further reduces absorption. After absorption, bisphosphonate uptake to the primary site of action is rapid and sustained. Once attached to bone tissue, bisphosphonates are released very slowly. These drugs are not metabolized and are excreted renally. They are not recommended for use in patients with renal insufficiency. 

Drug therapy individualization for patients with renal insufficiency sometimes requires only a simple proportional dose adjustment based on creatinine clearance (CLcr). Alternatively, complex adjustments are required for drugs that are extensively metabolized or undergo dramatic changes in protein binding and distribution volume. 

Caution Recommended doses do not apply for adult patients with body weight less than 50 kg. Recommended doses do not apply to patients with renal or hepatic insufficiency or other conditions affecting drug metabolism and kinetics. Starting doses should be lower for elderly patients. 

While essentially all ACE inhibitors have a similar mechanism of action and therefore exhibit similar efficacy in the treatment of hypertension and congestive heart failure, these drugs differ slightly in their pharmacokinetic profiles. Enalapril, lisinopril, and quinapril are excreted primarily by the kidney, with minimal liver metabolism, while the other prodrug compounds are metabolized by the liver and renally excreted. Thus, in patients with renal insufficiency, the half-life of renally excreted ACE inhibitors is prolonged. In addition, patients with impaired liver func-... 

Heparin s action is terminated by uptake and metabolism by the reticuloendothelial system and liver and by renal excretion of the unchanged drug and its de-polymerized and desulfated metabolite. The relative proportion of administered drug that is excreted as unchanged heparin increases as the dose increases. Renal insufficiency reduces the rate of heparin clearance from the blood. 

For parenteral therapy, nafciUin and oxacillin offer comparable efficacy and antimicrobial spectra of activity. Although both drugs undergo hepatic metabolism, only nafcillin requires dose adjustment in patients with combined hepatic and renal insufficiency. Other pharmacokinetic data for nafcillin and oxacillin appear in Table 45.1. Indications for nafcillin or oxacillin include severe staphylococcal infections like cellulitis, empyema, endocarditis, osteomyelitis, pneumonia, septic arthritis, and toxic shock syndrome. 

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). 

Nitrofurantoin is well absorbed after ingestion. It is metabolized and excreted so rapidly that no systemic antibacterial action is achieved. The drug is excreted into the urine by both glomerular filtration and tubular secretion. With average daily doses, concentrations of 200 mcg/mL are reached in urine. In renal failure, urine levels are insufficient for antibacterial action, but high blood levels may cause toxicity. Nitrofurantoin is contraindicated in patients with significant renal insufficiency. 

A potential drug interaction between simvastatin and danazol, causing rhabdomyolysis and acute renal insufficiency, has been reported (43). Rhabdomyolysis can occur with all statins when they are used alone and particularly when they are combined with other drugs that are themselves myotoxic or that increase the concentration of the statin. Statins are particularly susceptible to the latter effect because of their metabolism by the CYP450 system and their low oral systemic availability. 

Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, biguanides accumulate and thereby increase the risk of lactic acidosis, which appears to be a dose-related complication. 

Three agents are available ondansetron, granisetron, and dolasetron. The drugs have a long serum half-life of 4-9 hours and may be administered once or twice daily by oral or intravenous routes. The drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion. However, dose reduction is not required in geriatric patients or patients with renal insufficiency. For patients with hepatic insufficiency, dose reduction may be required with ondansetron. 

The pharmacokinetics of zaleplon in elderly subjects is not significantly different from that in young healthy subjects [38]. Nevertheless, Drover [39] contends that this conclusion may indicate a lack of adequate studies in this area. As described earlier, zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon is reduced, and the drug effect is prolonged in patients with hepatic impairment [40]. The clearance of zaleplon is not altered in patients with mild to moderate renal insufficiency [40] (Tab. 3). 

The use of nicorandil in elderly patients with chronic renal insufficiency and in patients with stable hepatic cirrhosis is not associated with any significant alteration in its pharmacokinetics. In addition, its metabolism is not affected by drugs that interfere with drug-metabohzmg liver enzymes (28). 

The main role of the kidney in the process of drug metabolism consists in the excretion of the many, more or less pharmacologically active metabolites formed in the liver [8]. Needles to say that renal insufficiency may result in the accumulation of metabohtes and, if pharmacological active, may result in serious side effects/ toxicity [33]. Renal metabolism of drug-xenobiotics and its contribution to elimination has been inadequately explored so that clinical implications are for the most part inferred from animal models or speculative. 

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