Serum Protein Binding of Phenytoin and Valproic Acid in Insulin-Dependent Diabetes Mellitus

Gatti, G.; Crema, Francesca; Attardo-Parrinello, Giuseppe; Fratino, P; Aguzzi, F; Perucca, Emilio

doi:10.1097/00007691-198712000-00005

Cited by 35 publications

(20 citation statements)

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“…The circulating concentrations of albumin and ai-acid glycoprotein do not appear to be different in diabetic patients and controls (Gatti et al 1987;Kearns et al 1988;McNamara et al 1988), so that this factor alone is unlikely to contribute to a change in drug binding. On the other hand, it is well known that free fatty acids (FFA) are elevated in the plasma of patients with either IDOM or NIDOM (Chase & Glasgow et al 1976;Fraze et al 1985 Adithan et al (1989a) served between the free fraction of valproic acid and serum FFA concentration (Gatti et al 1987). It is interesting to note that although the mean serum FFA concentration was higher in the diabetic patients, this difference failed to reach statistical significance.…”

Section: Distributionmentioning

confidence: 99%

The Effects of Diabetes Mellitus on Pharmacokinetics and Pharmacodynamics in Humans

Gwilt

Nahhas

Tracewell

1991

Clinical Pharmacokinetics

142

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The article reviews the effect of diabetes on the pharmacokinetics and pharmacodynamics of drugs in humans. For most drugs which cross the gastrointestinal wall by passive diffusion, oral absorption is unlikely to be affected by diabetes, although a delay in the absorption of tolazamide and a decrease in the extent of absorption of ampicillin have been reported. Subcutaneous absorption of insulin is more rapid in diabetic patients, whereas the intramuscular absorption of several drugs is slower. The binding of a number of drugs in the blood is reduced in diabetes, which may be due to glycosylation of plasma proteins or displacement by plasma free fatty acids, the level of which is increased in diabetic patients. Plasma concentrations of albumin and alpha 1-acid glycoprotein do not appear to be changed by the disease. The distribution of drugs with little or no binding in the blood is generally not altered, although the volume of distribution of phenazone (antipyrine) is reduced by 20% in insulin-dependent diabetes mellitus (IDDM). In contrast to animal studies, the metabolic clearance of most drugs in humans appears to be unaffected or slightly reduced by the disease. The presence of fatty liver in non-insulin-dependent diabetes mellitus (NIDDM) may contribute to a reduced hepatic clearance, whereas decreased binding in the blood may cause an increase in clearance. The effect of diabetes on hepatic blood flow in humans appears to be unknown. Diabetes affects kidney function in a significant number of diabetic patients. During the first 10 years after the onset of the disease, glomerular filtration is elevated in these patients. Thus, the renal clearance of a number of antibiotics has been shown to be increased in diabetic children. As the disease progresses, renal function is impaired and glomerular function declines from the initial elevated state. In diabetic adults the renal clearance of drugs either is comparable with that found in nondiabetic individuals or is reduced. A limited number of studies have been conducted comparing the dose-response of cardiovascular drugs in diabetic patients with that in nondiabetic controls. Decreased, increased and unchanged responses have been reported. It is apparent that in some cases an altered response may be observed for a drug when administered to a diabetic patient compared with a similar nondiabetic individual. At the present time, it is not possible to ascertain whether these studies reflect true pharmacodynamic changes or merely alterations in pharmacokinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Distributionmentioning

confidence: 99%

The Effects of Diabetes Mellitus on Pharmacokinetics and Pharmacodynamics in Humans

Gwilt

Nahhas

Tracewell

1991

Clinical Pharmacokinetics

142

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“…This could be due to increased free fatty acid level and/or glycosylation of albumin in diabetic rats [22,23].…”

Section: Measurement Of Plasma Protein Binding Using An Equilibrium Dmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of intravenous torasemide in diabetic rats induced by alloxan or streptozotocin

Kim

et al. 2005

Biopharm. Drug Dispos.

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The pharmacokinetic and pharmacodynamic parameters of torasemide were compared after intravenous administration at a dose of 2 mg/kg to diabetic rats induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. It was reported that torasemide was mainly metabolized via CYP2C11 in rats and the expression and mRNA level of CYP2C11 decreased in DMIA and DMIS rats. Hence, it could be expected that the time-averaged nonrenal clearance (Cl(nr)) of torasemide could be slower in the diabetic rats. As expected, the Cl(nr) values were significantly slower in DMIA (0.983 versus 1.35 ml/min/kg) and DMIS (0.998 versus 1.36 ml/min/kg) rats. However, the time-averaged renal clearance (Cl(r)) values of torasemide were significantly faster in DMIA (0.164 versus 0.0846 ml/min/kg) and DMIS (0.205 versus 0.0967 ml/min/kg) rats due to urine flow rate-dependent timed-interval Cl(r) of torasemide in rats. The comparable time-averaged total body clearance (Cl) values between the diabetic and control rats were due to partially compensated Cl(r) in the diabetic rats. The 8 h urine output and diuretic efficiency increased significantly in the diabetic rats due to significantly greater 8 h urinary excretion of unchanged torasemide and at least partly due to an increase in urine output in diabetes per se (without administration of any drugs).

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“…These modifications are of interest since past studies have suggested that the glycation of HSA can lead to alterations in the binding of this protein to drugs such as phenytoin, salicylate, ibuprofen, phenylbutazone and warfarin [8,[21][22][23][24]. Furthermore, the effect of glycation appears to vary between different binding regions on HSA [23,24].…”

Section: Introductionmentioning

confidence: 99%

Characterization of glycation adducts on human serum albumin by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

Cerny

Clarke³

et al. 2007

Clinica Chimica Acta

108

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Background-Non-enzymatic glycation of human serum albumin (HSA) is associated with the long-term complications of diabetes. We examined the structure and location of modifications on minimally glycated HSA and considered their possible impact on the binding of drugs to this protein.Methods-Minimally glycated and normal HSA (used as a control) were digested with trypsin, Glu-C or Lys-C, followed by fractionation of the resulting peptides and their analysis by matrixassisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) to determine the structures and locations of glycation adducts.Results-Several specific lysine and arginine residues were identified as modification sites in minimally glycated HSA. Residues K12, K51, K199, K205, K439 and K538 were found to be modified through the formation of fructosyl-lysine, while the modification of K159 and K286 involved the formation of pyrraline, N ε -carboxymethyl-lysine respectively. Lysine K378 was found to give N ε -carboxyethyl-lysine in some forms of glycated HSA but fructosyl-lysine in other forms. Residues R160 and R472 produced a modification based on N ε -(5-hydro-4-imidazolon-2-yl) ornithine. Lysine R222 was modified to produce argpyrimidine, N ε -[5-(2,3,4-trihydroxybutyl)-5-hydro-4-imidazolon-2-yl]ornithine or tetrahydropyrimidine.Conclusions-With the exception of K12, K199, K378, K439 and K525, all of the observed sites of modification for minimally glycated HSA were new to this current study. The fact that many of these glycation-related modifications are located at or near known drug binding sites on HSA explains why some differences have been previously noted in the binding of certain drugs to normal vs glycated HSA.

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Serum Protein Binding of Phenytoin and Valproic Acid in Insulin-Dependent Diabetes Mellitus

Cited by 35 publications

References 0 publications

The Effects of Diabetes Mellitus on Pharmacokinetics and Pharmacodynamics in Humans

The Effects of Diabetes Mellitus on Pharmacokinetics and Pharmacodynamics in Humans

Pharmacokinetics and pharmacodynamics of intravenous torasemide in diabetic rats induced by alloxan or streptozotocin

Characterization of glycation adducts on human serum albumin by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

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