Impaired Binding of Drugs and Endogenous Ligands in Renal Diseases

Gulyassy, Paul F.; Depner, Thomas A.

doi:10.1016/s0272-6386(83)80038-9

Cited by 82 publications

(39 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Early in the history of dialysis, it was recognized that protein binding impairs solute clearance (1,12 Dialysis is typically performed with values of K o A and Q d in the range of two-to threefold higher than Q p . This provides urea clearances in the range of 75% to 90% of dialyzer blood flow, because the dialyzer clears urea from red cells as well as from plasma (6).…”

Section: Discussionmentioning

confidence: 99%

“…On albumin, different solutes compete for binding at individual sites and some solutes bind to more than one site (9). Solute competition for protein binding sites has been described in renal failure, with illdefined uremic toxins displacing solutes such as tryptophan and phenytoin from albumin (12). Presumably, values for f for some solutes may decline during dialysis as competing solutes are removed.…”

Section: Discussionmentioning

confidence: 99%

“…Rewriting equation (7) in differential form and rearranging yields (12) so that equation (11) becomes…”

Section: Modeling the Effect Of Protein Binding On Dialytic Clearancementioning

confidence: 99%

See 2 more Smart Citations

Increasing Dialysate Flow and Dialyzer Mass Transfer Area Coefficient to Increase the Clearance of Protein-bound Solutes

Meyer¹,

Leeper²,

Bartlett

et al. 2004

Journal of the American Society of Nephrology

103

116

View full text Add to dashboard Cite

Abstract. Clinical hemodialysis systems achieve high single pass extraction of small solutes that are not bound to plasma proteins. But they clear protein-bound solutes much less effectively. This study examines the extent to which clearance of a protein-bound test solute is improved by increasing the dialyzer mass transfer area coefficient (K o A) and the dialysate flow rate (Q d Protein-bound solutes are poorly cleared during conventional hemodialysis (1-4). Accumulation of such solutes may contribute to residual uremic disorders when levels for dialytic clearance of urea and other small, unbound solutes are considered "adequate" (3-5). The dialytic clearance of an unbound solute is determined by the blood flow rate, Q b , the dialyzer mass transfer area coefficient, K o A, for that solute, and the dialysate flow rate, Q d (6). In conventional practice, K o A and Q d are set to achieve values for urea clearance close to Q b . Further increases in K o A and Q d cannot significantly increase urea clearance and are therefore generally not contemplated.The study presented here examined whether the clearance of protein-bound solutes could, by contrast, be improved by increasing K o A and Q d relative to the plasma flow rate, Q p . In vitro dialysis experiments measured the clearance of phenol red, a small solute strongly bound to albumin, from artificial plasma. As expected, the clearance of phenol red was much lower than the clearances of the unbound solutes, urea and creatinine. Phenol red clearance could, however, be increased by increasing both K o A and Q d . We developed a mathematical model to predict the clearance of a protein-bound solute from Q p , Q d , K o A, the albumin concentration, and the association constant, K A , that describes the strength of solute binding to albumin. Mathematical modeling accurately predicted the pattern of measured results and showed further that clearance values for tightly protein-bound solutes can be made to approach Q p by significantly increasing K o A and Q d . Materials and Methods Clearance Measurements during In Vitro DialysisModel Dialysis System. Clearances of phenol red, urea, and creatinine were measured during dialysis in vitro. Fluid representing a patient's plasma was placed in a continuously stirred 4.5 L reservoir and dialyzed with a Fresenius D machine (Fresenius, Gurnee, IL). The reservoir and dialysate fluids were prepared to have identical free electrolyte concentrations, which approximated Na 140 mEq/L, K 4.0 mEq/L, HCO 3 24 mEq/L, Mg 2.0 mEq/L, Ca 2.5 mEq/L, and PO 4 4.0 mg/dl. Fluid preparation comprised addition of small amounts of KCl, MgCl 2 , and CaCl 2 to Fresenius 6615 acid concentrate and NaH 2 PO 4 to 1.0 M NaHCO 3 concentrate solutions. These solutions were then mixed and appropriately diluted by the dialysis machine. Addition of reagent phenol red, urea, and creatinine to the reservoir provided concentrations of approximately 3.0 mg/dl, 120 mg/dl, and 12.0 mg/dl, respectively, at the beginning of each dialysis run. Dialysis experiments en...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Increasing Dialysate Flow and Dialyzer Mass Transfer Area Coefficient to Increase the Clearance of Protein-bound Solutes

Meyer¹,

Leeper²,

Bartlett

et al. 2004

Journal of the American Society of Nephrology

103

116

View full text Add to dashboard Cite

show abstract

“…9) However, in fact, renal failure has a variety of influences on drug kinetics: it reduces nonrenal drug elimination (which includes renal as well as hepatic drug metabolism), and influences protein binding and alters the volume of distribution of some drugs. [10][11][12] Renal failure reduces the bioavailability of some drugs and increases that of others. Even for drugs which are not renally eliminated, renal failure can lead to the accumulation of toxic metabolites.…”

mentioning

confidence: 99%

Effect of Experimental Renal Failure on the Pharmacokinetics of Losartan in Rats.

Yoshitani

Yagi

Inotsume

et al. 2002

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Losartan is a potent, orally active, angiotensin II receptor antagonist and is used as an antihypertensive agent.1) Losartan binds selectively and specifically to the AT 1 subtype of angiotensin receptor. In contrast to angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists directly abolish the actions of angiotensin II in the body.Losartan is metabolized to EXP3174, 2-n-butyl-4-chloro-1-[(2Ј-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole-5-carboxylic acid, which contributes to the overall in vivo activity of losartan in rats 2) and humans.3) EXP3174 has a longer half-life than losartan. The conversion of losartan to EXP3174 is catalyzed by two cytochrome P450 subfamilies: CYP2C9 and CYP3A4. 4) In normal volunteers, renal clearance accounts for about 12 and 55% of the systemic clearance of losartan and EXP3174, respectively. 5)Progressive renal insufficiency is commonly accompanied by hypertension, which frequently results in the use of antihypertensive agents to reduce blood pressure or, secondarily, to provide renoprotection 6) ; accordingly, it is necessary to investigate the effect of renal failure on the pharmacokinetics of antihypertensive drugs to establish when dosage adjustment is necessary. Very limited information is available on the pharmacokinetics of losartan in humans with renal dysfunction. Sica et al. reported that the steady-state areas under the curve (AUC) of losartan and EXP3174 were not significantly changed with renal impairment. 7) On the other hand, Saruta et al. reported that the maximum serum concentration (C max ) and AUC 0-24 in patients with renal impairment were higher than those in patient with normal renal function. 8)Renal failure is commonly thought to have its sole effect on the renal elimination of drugs.9) However, in fact, renal failure has a variety of influences on drug kinetics: it reduces nonrenal drug elimination (which includes renal as well as hepatic drug metabolism), and influences protein binding and alters the volume of distribution of some drugs.10-12) Renal failure reduces the bioavailability of some drugs and increases that of others. Even for drugs which are not renally eliminated, renal failure can lead to the accumulation of toxic metabolites.9)The purpose of this investigation was to determine the effects of experimental renal failure on the pharmacokinetics of losartan in rats. Animals Male Wistar rats (8 weeks) weighting 250-302 g, were purchased from SLC Japan (Hamamatsu). Before the experiments, the rats were housed in a temperature-and humidity-controlled room with free access to water and standard rat chow. The animal experiments were performed in accordance with The Guidelines for Animal Experiments of Tokyo Medical and Dental University. MATERIALS AND METHODS MaterialsInduction of Acute Renal Failure To produce experimental acute renal failure (ARF), rats received a subcutaneous injection of uranyl nitrate, 10 mg/kg as a 1% solution in normal saline, about 72 h before the experiment. 13) Control animals received an injecti...

show abstract

“…Protein binding also serves to protect the host by minimizing the free (unbound) and presumably toxic species. Failure of dialysis to remove albumin-bound compounds is clearly demonstrated by chromatographic techniques that show high concentrations of bound solutes in well dialyzed uremic serum (15), and by the reduced potential of uremic albumin to bind marker solutes, evidence that the binding sites are highly saturated (16,17). The albumin-binding defect itself could have adverse consequences independent of the toxicity of accumulated ligands if transport of other vital but not necessarily toxic substances is impaired.…”

mentioning

confidence: 99%