Renal role, pharmacokinetics

Renal elimination of unchanged drug accounts for 66% of drug clearance, and the dose should be adjusted for impaired renal function. The role of therapeutic drag monitoring is unknown. It has linear pharmacokinetics and is metabolized in blood by nonhepatic enzymatic hydrolysis. 

Active transporters are thought to play an important role in the pharmacokinetics of drugs, not only because they can regulate the permeability of drugs as substrate-specific efflux or influx pumps, but also because of their widespread presence across in vivo membrane systems, from the intestinal epithelia to the BBB. Generally speaking, the absorption direction transporters tend to have narrower substrate specificity than the excretion direction transporters. Active transporters also play a significant role in biliary and renal excretion. 

Subach RA, Marx MA. Drug dosing in acute renal fail-ure the role of renal replacement therapy in altering drug pharmacokinetics. Adv Renal Repl Ther 1997 5 141-7. 

Figure 7.6 Structure of remifentanil and its major metabolite formed by ester hydrolysis. contrast, alfentanil has an intermediate hepatic extraction (0.3-0.5) and alfentanil clearance will be sensitive to changes in both liver blood flow and reduced enzyme capacity in patients with liver disease. Although the kidneys play a minor role in the elimination of most opioids, renal disease can influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is significantly altered in patients with liver or renal disease.

Koup JR, Jusko WJ, Elwood CM, KohU RK. Digoxin pharmacokinetics Role of renal failure in dosage regimen design. CUn Pharmacol Ther 1975 18 9-21. 

Interferon-o, a 165 amino acid glycoprotein, is effective in the treatment of viral hepatitis C and B, myeloma, melanoma, and renal carcinoma. Little is known about the renal metabolism of interferon-a despite extensive studies in experimental animals. In patients with normal renal function, the serum peak level occurs 8 hours after a subcutaneous injection of 3x10 units of interferon-a. Terminal elimination half-life ranges from 4 to 16 hours and after 24 to 48 hours, the interferon molecule is undetectable in the serum [181]. A-interferon urinary level is undetectable. Some authors have suggested that, despite the lack of urinary excretion, the kidney could play a role in interferon-a metabolism [182]. Indeed, as far as hepatitis C treatment is concerned, dialysis patients often show a better response to therapy than non-dialysis patients. This better efficacy in dialysis patients is associated with an increase of the incidence of adverse effects. This observation raises the question of pharmacokinetic modifications. One study documented that clearance kinetics of interferon-a in patients with chronic renal failure are about half the rate of patients with normal renal function [183]. Indeed interferon is filtered by the glomeruli and largely absorbed and catabolized within tubular cells [184]. 

The incidence of phenytoin toxicity may be increased in the eideriy, or in those patients with hepatic or renal impairment, because of alterations in its pharmacokinetics. Plasma level determinations may be indicated in these cases. Although a role for P-glycoprotein transporter alleles in the development of phenytoin toxicity remains controversial, phenytoin is a robust substrate for the non-ABC efflux transporter RLIP76. Because RLIP76 has been found to be overexpressed in excised human epileptic foci, its action may account for treatment failures conversely, inhibition of transport may cause toxicity (34). There is a 2 to 3% increase in the risk of fetal epilepsy syndrome if the mother is taking phenytoin. Phenytoin is contraindicated in cardiac patients with bradyarrhythmias. Induction of CYP2C19 by ginkgo biloba may increase phenytoin clearance and precipitate serious seizures (35). 

Ings RMJ, Reeves DS, White LO, Bax RP, Bywater MJ, Holt HA. The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secreticMi on iheii elimmation. JPharmacokinetBiof arm 1985) 13, 121-42. 

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