Pharmacokinetic Profile of Dodecanedioic Acid, a Proposed Alternative Fuel Substrate

Abstract

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.

Approximate linear confidence and curvature of a kinetic model of dodecanedioic acid in humans

“…This form of administration is safe (8,18), inexpensive, and practical because of C12 water solubility and good tolerability of peripheral vein infusion.…”

“…Preliminary studies in rats (18) showed that only 3.9% of C12 administered as an intravenous bolus is lost with urine, that its half-life is short (12.47 min), and that its systemic clearance is good (0.0138 liter⅐kg body wt Ϫ1 ⅐min Ϫ1 ); in addition, the low C12 renal clearance indicates tubular reabsorption of dodecanedioic acid.…”

Medium-Chain, Even-Numbered Dicarboxylic Acids as Novel Energy Substrates: An Update

“…In fact, the urinary excretion of C12 is low (3%-5% of administered dose) 33,34 compared with azelaic acid (dicarboxylic acid with nine carbon atoms) 35 and sebacic acid (dicarboxylic acid with 10 carbon atoms), 36,37 and the energy density is high (7.18 kcal/g of C12 oxidized). 33 The C12 respiratory quotient (0.77) is rather low, representing an advantage in patients with respiratory distress, in whom CO 2 pulmonary exchange is low with subsequent hypercapnia and acidosis. Furthermore, the free fraction of C12 in plasma is higher than the fraction of both long-and medium-chain monocarboxylic acids, in view of its relatively high water solubility and its low affinity for albumin-binding sites.…”

Medium-Chain, Even-Numbered Dicarboxylic Acids as Novel Energy Substrates: An Update

“…In fact, the urinary excretion of C12 is low (3%-5% of administered dose) 33,34 compared with azelaic acid (dicarboxylic acid with nine carbon atoms) 35 and sebacic acid (dicarboxylic acid with 10 carbon atoms), 36,37 and the energy density is high (7.18 kcal/g of C12 oxidized). 33 The C12 respiratory quotient (0.77) is rather low, representing an advantage in patients with respiratory distress, in whom CO 2 pulmonary exchange is low with subsequent hypercapnia and acidosis. Furthermore, the free fraction of C12 in plasma is higher than the fraction of both long-and medium-chain monocarboxylic acids, in view of its relatively high water solubility and its low affinity for albumin-binding sites.…”