Binding of straight-chain saturated dicarboxylic acids to albumin.

Tonsgard, James H.; Mendelson, Stephen; Meredith, Stephen C.

doi:10.1172/jci113767

Cited by 17 publications

(20 citation statements)

References 22 publications

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“…However, a caution should also be raised, as HDA and TDA were found to be associated with drug-metabolizing enzyme CYP4A11 and renal transporters OAT1 and OAT3, reflecting complexity of HDA and TDA disposition and potential difficulty in using them as OATP-specific endogenous biomarkers, in particular when a perpetrator drug inhibits multiple transporters (Yee et al, 2016). It is also worth noting that, although the functions of HDA and TDA are not fully understood, the serum concentrations of HDA, TDA, and other dicarboxylic acids are increased in patients with diseases, such as Reye syndrome, caused by an insult to fatty acid dmd.aspetjournals.org metabolism and (or) stimulation of omega-oxidation (Tonsgard, 1986(Tonsgard, , 1988.…”

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confidence: 99%

Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects

Shen

Chen

Drexler

et al. 2017

Drug Metabolism and Disposition

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Multiple endogenous compounds have been proposed as candidate biomarkers to monitor organic anion transporting polypeptide (OATP) function in preclinical species or humans. Previously, we demonstrated that coproporphyrins (CPs) I and III are appropriate clinical markers to evaluate OATP inhibition and recapitulate clinical drug-drug interactions (DDIs). In the present study, we investigated bile acids (BAs) dehydroepiandrosterone sulfate (DHEAS), hexadecanedioate (HDA), and tetradecanedioate (TDA) in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs. All probes were determined in samples from a single study that examined their behavior and their association with rosuvastatin (RSV) pharmacokinetics after administration of an OATP inhibitor rifampin (RIF) in healthy subjects. Among endogenous probes examined, RIF significantly increased maximum plasma concentration () and area under the concentration-time curve (AUC) of fatty acids HDA and TDA by 2.2- to 3.2-fold. For the 13 bile acids in plasma examined, no statistically significant changes were detected between treatments. Changes in plasma DHEAS did not correlate with OATP1B inhibition by RIF. On the basis of the magnitude of effects for the endogenous compounds that demonstrated significant changes from baseline over interindividual variations, the overall rank order for the AUC change was found to be CP I > CP III > HDA ≈ TDA ≈ RSV > > BAs. Collectively, these results reconfirmed that CPs are novel biomarkers suitable for clinical use. In addition, HDA and TDA are useful for OATP functional assessment. Since these endogenous markers can be monitored in conjunction with pharmacokinetics analysis, the CPs and fatty acid dicarboxylates, either alone or in combination, offer promise of earlier diagnosis and risk stratification for OATP-mediated DDIs.

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confidence: 99%

Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects

Shen

Chen

Drexler

et al. 2017

Drug Metabolism and Disposition

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“…We assumed that azelaic acid is almost completely free in serum, in view of the results from Tonsgard et al (1988) showing that the affinity for albumin of the superior homologue of azelaic acid (sebacic acid) is markedly smaller than that of monocarboxylic fatty acids. Thus it is likely that, in our experimental conditions, the albumin binding sites are saturated by fatty acids as well as by other substances (e.g.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Analysis of Azelaic Acid Disodium Salt

Bertuzzi

Gandolfi

Salinari

et al. 1991

Clinical Pharmacokinetics

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Azelaic acid was the first dicarboxylic acid proposed as an alternative energy substrate in total parenteral nutrition. In this study, the pharmacokinetics of azelaic acid were investigated in 12 healthy volunteers, 7 receiving a constant infusion (10g over 90 min) and 5 a bolus dose (1g). The 24h urinary excretion and plasma concentration in blood samples taken at regular intervals were assayed by gas-liquid chromatography. Experimental data were analysed by a 2-compartment nonlinear model that describes both tubular secretion and cellular uptake in Michaelis-Menten terms. A high value of urinary excretion (mean 76.9% of infused dose) and a mean clearance of 8.42 L/h were found, suggesting the presence of tubular secretion. Estimating the population mean of the pharmacokinetic model parameters gave a maximal cellular uptake of 0.657 g/h. The model predicts that 90% of the maximal uptake should be reached in the plateau phase of a constant infusion of 2.2 g/h. The presence of extensive and rapid losses through urinary excretion, and the low estimated value of the maximal cellular uptake, indicate that azelaic acid is not suitable as an energy substrate for total parenteral nutrition.

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“…Albumin Binding Model Dodecanedioic binding in plasma was assessed by a one-site model (Table I) according to the methods of Tonsgard and Meredith.' 7 The model was fitted by unweighted nonlinear least squares, using the inverse Hessian method to derive the estimates of the parameter dispersions. A two-site model was not shown to be superior to the one-site model for explaining the binding curve.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Pharmacokinetic Profile of Dodecanedioic Acid, a Proposed Alternative Fuel Substrate

Mingrone

Greco

Gaetano

et al. 1994

J Parenter Enteral Nutr

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Dodecanedioic acid (C12), a saturated, aliphatic dicarboxylic acid with 12 carbon atoms, was given as an intravenous bolus (800 mumol/kg of body weight [kgBW]) in male Wistar rats to study its pharmacokinetic profile. Because total plasma C12, which results from the sum of both free and albumin binding fractions, was measured by high-performance liquid chromatography, an in vitro experimental session was carried out to determine the binding curve of C12 in rat plasma. These data were then used to calculate the plasma C12 free fraction in in vivo experiments. The best fit obtained for the experimental data of albumin binding was obtained with the equation of reversible, saturable binding to one, two, or three classes of noninteracting equivalent sites. Only a single binding site was clearly identified with a dissociation constant of 147 mumol/L and a maximal predicted binding of 1.57 mol/mol albumin. The urinary excretion of C12 was 3.90 +/- 1.62% of the administered dose. The pharmacokinetic analysis was performed by one-compartment model with linear transfer to the tissues, taking into account simultaneously both plasma concentration and urine excretion data. The apparent volume of distribution of C12 was 0.248 +/- 0.035 L/kgBW, the apparent first order rate constant to the tissues was 0.0535 +/- 0.0123 min-1 and that from plasma to urine was 0.00206 +/- 0.00051 min-1. The C12 plasma half-life was 12.47 minutes. Renal clearance was 0.00051 L/kgBW per minute, whereas the systemic clearance was 0.0138 L/kgBW per minute. Because the renal clearance was much less than the rat inulin clearance reported in literature, the presence of C12 passive back-diffusion was hypothesized.

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Binding of straight-chain saturated dicarboxylic acids to albumin.

Abstract: Dicarboxylic acids are prominent features of several diseases,

Cited by 17 publications

References 22 publications

Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects

Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects

Pharmacokinetic Analysis of Azelaic Acid Disodium Salt

Pharmacokinetic Profile of Dodecanedioic Acid, a Proposed Alternative Fuel Substrate

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