Nonrenal clearance

Total drug clearance is the sum of nonrenal clearance and renal clearance (Clren). According to the MDRD-2 formula, the estimated GFR (eGFR) is a function of serum creatinine (SCr in mg/dl) and age (Age in years). It has the unit ml/min per 1.73 mA2. 

ARF patients may have a higher residual nonrenal clearance than CKD patients with similar creatinine clearances this complicates drug therapy individualization, especially with RRTs. 

CKD may alter nonrenal clearance of drugs as the result of changes in cytochrome P450-mediated metabolism in the hver and other organs. The clinical reductions in nonrenal clearance in CKD are generally proportional to the reductions in glomerular filtration rate (Table 77-1). 

TABLE 77-1 Effect of End-Stage Renal Disease on Nonrenal Clearance of Selected Drugs ... 

The rate of metabolism of nicotine can be determined by measnring blood levels after administration of a known dose of nicotine (Table 1) (Hukkanen et al. 2005c). Total clearance of nicotine averages about 1200 ml min . Nonrenal clearance represents about 70% of liver blood flow. Assuming most nicotine is metabolized by the hver, this means that about 70% of the drug is extracted from blood in each pass through the hver. 

Excretion - Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. The renal clearance of linezolid is low and suggests net tubular reabsorption. 

Well absorbed from the GI tract. Protein binding 91% 97%. Partially metabolized in the liver. Primarily excreted in urine (nonrenal clearance increases in severe renal impairment). Not removed by hemodialysis. Half-life 30-90 min (increased in renal or hepatic impairment). 

It is rapidly absorbed after oral administration. Approximately 40 percent of stavudine appears unchanged in the urine through tubular secretion and glomerular filtration. Nonrenal clearance mechanisms account for about 50 percent of elimination of a dose. 

Diltiazem [P] Increased plasma digoxin (usually 20-30%) due to reduced renal and nonrenal clearance. 

The interaction between ZDV and probenecid has been extensively studied in vitro and in several species. The interaction is complex. Probenecid inhibits the renal tubular secretion of both ZDV and ZDV glucuronide. Probenecid also directly affects the glucuronidation step, thus decreasing the nonrenal clearance of ZDV. For example, the nonrenal clearance of ZDV was significantly... 

Renal clearance accounts for 61% of the total body clearance of ciprofloxacin in humans (350). Coadministration of probenecid reduces the total body and renal clearance to 59% and 36% of the control value, respectively, but has no effect on the nonrenal clearance (336). The transporters involved in the renal elimination of ciprofloxacin remains unknown. 

The effects of cyclosporin A on the pharmacokinetics of etoposide have been determined and were shown to be dose dependent. A variable range of cyclosporin A concentrations was obtained (297-5073 ng/mL), and it was observed that patients with higher cyclosporin A concentrations also had larger increases in etoposide AUC (290). Results from studies using clinically relevant plasma concentrations of cyclosporin A (1000-5000 ng/mL) as a P-gp inhibitor resulted in mean 48%, 52%, and 52% decreases in the systemic, renal, and nonrenal clearances of intravenously administered etoposide (232,290). Similar decreases in the systemic, renal, and nonrenal clearances of doxorubicin were observed with administration of cyclosporin A (232,291). 

Figure 11.3. Loadings plot forthe 2-component PLS model for RankUrine, RankPPB, nonrenal clearance for N = 283 drugs.

The paucity of QSAR studies in whole animals is understandable in terms of the costs, the heterogeneity of the biological data, and the complexity of the results. Nevertheless, in the few studies that have been done, excellent QSAR have been obtained, despite the small number of subjects in the data set (164). One particular example is insightful. The renal and nonrenal clearance rates of a series of 11 jS-blockers, including bufuralol, tolamolol, propranolol, alprenolol, oxprenolol, acebutol, timolol, metoprolol, prindolol, atenolol, and nadolol were measured (230). The following QSAR were formulated using those data (164). 

It is apparent from QSAR 1.106 and 1.107, that the hydrophobicrequirements of the substrates vary considerably. As expected, renal clearance is enhanced in the case of hydrophilic drugs, whereas nonrenal clearance shows a strong dependency on hydrophobic-ity. Note that QSAR 1.107 is stretching the limits of the bilinear model with only 10 data points The 95% confidence intervals are also large but, nevertheless, the equations serve to emphasize the difference in clearance mechanisms that are clearly linked to hydrophobicity. 

FIGURE 4.5 Multicompartment system used to model the kinetics of NAPA absorption, distribution, and elimination. NAPA labeled with was injected intravenously (IV) to define the kinetics of NAPA disposition. NAPA distribution from intravascular space (Vq) to fast (Vp) and slow (Vg) equilibrating peripheral compartments is characterized by the intercompartmental clearances CLp and CLg. NAPA is cleared from the body by both renal (CLj ) and nonrenal (CLjyj ) mechanisms. A NAPA tablet was administered orally with the intravenous dose to analyze the kinetics of NAPA absorption from the gastrointestinal (GI) tract. After an initial delay that consisted of a time lag (not shown) and presumed delivery of NAPA to the small bowel (feg), the rate and extent of NAPA absorption were determined by ka and ko, as described in the text. (Reproduced with permission from Atkinson AJ, Jr. et al. Clin Pharmacol Ther 1989 46 182-9.)... 

Nonrenal clearance is usually equated with drug metabolism, but also could include hemodialysis and other methods of drug removal. In fact, even the metabolic clearance of a drug frequently consists of additive contributions from several parallel metabolic pathways. The characterization of drug metabolism by a clearance term usually is appropriate, since the metabolism of most drugs can be described by first-order kinetics within the range of therapeutic drug concentrations. 

The nonrenal clearance of the drug remains constant when renal function is impaired. 

Most drugs are not excreted unchanged by the kidneys but first are biotransformed to metabolites that then are excreted. Renal failure not only may retard the excretion of these metabolites, which in some cases have important pharmacologic activity, but, in some cases, alters the nonrenal as well as the renal metabolic clearance of drugs (15, 24). The impact of impaired renal function on drug metabolism is dependent on the metabolic pathway, as indicated in Table 5.2. In most... 

Because elimination clearances are additive/ total solute clearance during hemodialysis (CLp) can be expressed as the sum of dialysis clearance (CLd), and the patienfs renal clearance (CLr) and nonrenal clearance (CLjvp) ... 

Macias WL, Mueller BA, Scarim KS. Vancomycin pharmacokinetics in acute renal failure Preservation of nonrenal clearance. Clin Pharmacol Ther 1991 50 688-94. 

Hepatic clearance (CLh) may be defined as the volume of blood perfusing the liver that is cleared of drug per unit time. Usually, hepatic clearance is equated with nonrenal clearance and is calculated as total body clearance (CLe) minus renal clearance (CLr) ... 

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