Effects of Surfactants on Amiodarone Intestinal Absorption. I. Sodium Laurylsulfate

Amiodarone is a widely used antiarrhythmic agent with high variability in therapeutic effects, which appears to be related, at least in part, to its pharmacokinetics, and in particular, gastrointestinal absorption. The drug exhibits physico-chemical properties highly suitable for diffusion across lipophilic absorbing membranes but its low aqueous solubility can act as the rate limiting step for absorption, making it erratic and variable. In studying the intestinal absorption mechanism of amiodarone, a series of experiments using a rat gut in situ preparation was performed in the presence of a synthetic anionic surfactant, as a drug solubilizer, i.e., sodium laurylsulfate, at variable supramicellar concentrations (from 2.6 to 104 mM). Absorption rate constants of amiodarone decreased as surfactant concentration increased, the absorption being unusually fast at lower surfactant concentrations. Equations were developed to evaluate the relationship between absorption rate constant and surfactant concentration in the intestinal luminal fluid.     

The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone

Two-pore-domain (K_2P) potassium channels mediate background potassium currents, stabilizing resting membrane potential and expediting action potential repolarization. In the heart, K_2P3.1 (TASK-1) channels are implicated in the cardiac plateau current, I _KP . Class III antiarrhythmic drugs target cardiac K⁺ currents, resulting in action potential prolongation and suppression of atrial and ventricular arrhythmias. The objective of this study was to investigate acute effects of the class III antiarrhythmic drug amiodarone on human K_2P3.1 channels. Potassium currents were recorded from Xenopus oocytes using the two-microelectrode voltage clamp technique. Amiodarone produced concentration-dependent inhibition of hK_2P3.1 currents (IC₅₀ = 0.40 μM) with maximum current reduction of 58.1%. Open rectification properties that are characteristic to hK_2P3.1 currents were not altered by amiodarone. Channels were blocked in open and closed states in reverse frequency-dependent manner. hK_2P3.1 channel inhibition was voltage-independent at voltages between −40 and +60 mV. Modulation of protein kinase C activity by amiodarone does not contribute to hK_2P3.1 current reduction, as pre-treatment with the protein kinase C inhibitor, staurosporine, did not affect amiodarone block. Amiodarone is an inhibitor of cardiac hK_2P3.1 background channels. Amiodarone blockade of hK_2P3.1 may cause prolongation of cardiac repolarization and action potential duration in patients with high individual plasma concentrations, possibly contributing to the antiarrhythmic efficacy of the class III drug.     

Comparative analysis of the experimental and clinical pharmacokinetics of Amiodarone

The pharmacokinetics of two tablet formulations of amiodarone – Amiodarone and Amiodaron-Akri – were studied in 12 rabbits and 18 healthy human volunteers after single p.o. doses of 200 mg. A highly statistically significant correlation was found between plasma amiodarone concentrations in rabbits and volunteers (r = 0.8263, p < 0.001). Normalized C _max and AUC _0−∞ values were significantly greater in volunteers than rabbits, while specific V _Z and Cl _t values were lower and MRT was significantly higher; rate coefficients of absorption and measures of relative bioavailability showed no statistically significant differences between rabbits and healthy humans.     

Amiodarone is a potent calmodulin antagonist

Summary The possible interaction between amiodarone, a potent antiarrhythmic and antianginal agent, and calmodulin (CaM) was investigated by three avenues of approach: (a) Effect of amiodarone on cardiac and vascular Ca²⁺/calmodulin-activated cyclic nucleotide phosphodiesterase (CaM-PDE); (b) Effect on the CaM-activated (Ca²⁺ + Mg²⁺)-ATPase from human erythrocytes; (c) Direct interaction between amiodarone and calmodulin measured by the effect of the drug on the fluorescence of 9-anthroylcholine (9AC) bound to calmodulin. Results show that amiodarone did not interact with basal activities of CaM-PDE and other isolated CaM-insensitive PDE forms as well as with (Ca²⁺ + Mg²⁺)-ATPase. Amiodarone inhibited calmodulin-activation of aortic CaM-PDE (K _i = 650 nM, substrate cGMP) and calmodulin-activation of erythrocyte ghosts (Ca²⁺ + Mg²⁺)-ATPase (IC₅₀ = 4.5 M) in an apparently competitive manner. Amiodarone decreased the fluorescence of the hydrophobic probe 9AC bound to calmodulin (IC₅₀ = 5 M).It is concluded that amiodarone is a potent calmodulin antagonist.     

In vitro study on the pulmonary cytotoxicity of amiodarone

Abstract

Context: Amiodarone (an iodinated benzofuran) is a Class III antiarrhythmic drug that produces significant pulmonary disease. Proposed mechanisms of this cytotoxicity include necrosis, apoptosis, mitochondrial dysfunction and glutathione depletion.

Objective: This study was designed primarily to explore whether amiodarone impairs lung tissue cellular bioenergetics in BALB/c and Taylor Outbred mice.

Materials and methods: Cellular respiration (mitochondrial O₂ consumption), ATP, caspase activity and glutathione were measured in lung fragments incubated in vitro with 22?µM amiodarone for several hours.

Results: Without amiodarone, lung tissue cellular mitochondrial O₂ consumption decayed exponentially with time, showing two distinct phases sharply separated at t?≥?150?min. The rate of cellular respiration was 6–10-fold higher in the late phase compared to the early phase (p?<?0.0001). Lung tissue ATP also decayed exponentially with time, suggesting “uncoupling oxidative phosphorylation” was the responsible mechanism (low cellular ATP with high mitochondrial O₂ consumption, resulting in rapid depletion of cellular metabolic fuels). Although intracellular caspase activity increased exponentially with time, the uncoupling was not prevented by the pancaspase inhibitor zVAD-fmk (N-benzyloxycarbonyl-val-ala-asp (O-methyl)-fluoromethylketone). The same profiles were noted in the presence of amiodarone; but cellular ATP decayed 50% faster. Cellular glutathione for untreated tissue was 560?±?287?pmol?mg^?1 (n?=?12) and for treated tissue was 490?±?226?pmol?mg^?1 (n?=?12, p?=?0.5106).

Conclusion: Uncoupling oxidative phosphorylation was demonstrated in untreated mouse lung tissues. Amiodarone lowered cellular ATP. Further studies are needed to explore the susceptibility of the lung to these deleterious insults and their relevance to human diseases.     

Impact of amiodarone on the ability of anterior fat pad retention to prevent postcoronary arterial bypass grafting atrial fibrillation incidence: a substudy of the AFIST III (Atrial Fibrillation Suppression Trial III)

Background: In the AFIST III (Atrial Fibrillation Suppressions Trial III), anterior fat pad (AFP) retention did not decrease the incidence of postoperative atrial fibrillation (POAF), but prophylaxis with amiodarone did. In order to examine the inter-relationship between amiodarone with AFP retention on POAF, we performed a planned subgroup analysis of AFIST III. Methods: Coronary artery bypass graft (CABG) patients were randomized to AFP maintenance or removal with prophylactic amiodarone used via the discretion of the caregiver. Patients were categorized into four groups: AFP retention alone, AFP retention plus amiodarone, AFP removal alone and AFP removal plus amiodarone. Multivariate logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals for development of POAF. Results: Amiodarone was used in 28% of the 178 patients (mean age = 66 ± 10, 80% male, 5% previous atrial fibrillation) undergoing CABG surgery. The overall POAF occurrence rate, regardless of subgroup designation was 35.4%. On multivariate logistic regression, amiodarone plus AFP retention was associated with an 81% reduction in the odds of the patient developing POAF (p = 0.015). Amiodarone prophylaxis without AFP retention was associated with a 68% reduction (p = 0.040). Conclusion: Amiodarone prophylaxis with or without AFP retention is an independent negative predictor of POAF. Combining amiodarone with AFP retention may provide a synergistic effect in the prevention of POAF. Further studies are needed to validate the results of this study.     

Amiodarone N‐Deethylation by CYP2C8 and its Variants,CYP2C8*3 and CYP2C8 P404A

Abstract: Amiodarone is a potent Class III antiarrhythmic drug. The N‐deethylation of amiodarone to desethylamiodarone is known to be catalyzed by cytochrome P450 (CYP) 2C8. In the present study, amiodarone N‐deethylation by the CYP2C8s, CYP2C8*1 (wild‐type), CYP2C8*3, and CYP2C8 P404A (Pro404Ala substitution in exon 8), was investigated by their transient expression in Hep G2 cells. The expression levels of CYP2C8*1 and CYP2C8*3 were similar, whereas the level of CYP2C8 P404A was 55.6% of that of CYP2C8*1. The kinetic parameters of amiodarone N‐deethylation were obtained by means of Lineweaver‐Burk analysis. The intrinsic clearance (V_max/K_m, per mg of microsomal protein) of amiodarone by CYP2C8 P404A but not CYP2C8*3 was significantly (48.7%) less than that of CYP2C8*1. These results suggest that CYP2C8 P404A but not CYP2C8*3 is less effective in the N‐deethylation of amiodarone.     

Pharmacokinetic Analysis of Drug Absorption from Muscle Based on a Physiological Diffusion Model: Effect of Molecular Size on Absorption

In a rabbit hind leg perfusion experiment, the absorption of radiolabeled water and carbohydrates of various molecular sizes from muscle was analyzed using a physiological diffusion model and, also, by statistical moment analysis. The model takes into account diffusion in the interstitial space, transcap-illary movement, and removal by the blood circulation and pharmacokinetic parameters representing these processes were computed by curve-fitting. The apparent diffusion coefficients of water and small sugars in the interstitial space (D _m) were proportional to their free diffusion coefficients in water (D _t), whereas the diffusion of ¹⁴C-inulin was hampered by interstitial structures. The first moments of each absorption process were also determined to assess the quantitative contribution of each absorption process to overall absorption. For carbohydrate molecules, residence time in the depot (t _d) accounted for most of the absorption time after injection, whereas for ³H-water, residence times in muscle (t_m) and in the depot (t_d) were similar.     

A theoretical consideration of percutaneous drug absorption

The percutaneous drug absorption process and its clinical significance are not fully known. In this article we propose a theoretical method to obtain two parameters (k _d and k_c) of percutaneous drug absorption from in vivodata. These parameters are related to diffusion of a drug through the skin and removal process at the skin-capillary boundary, respectively, characterizing several pharmacokinetic aspects of the drug applied to the skin. Moreover, by employing these two kinetic constants, a simulation of percutaneous drug absorption can be theoretically generated. On the basis of our theoretical considerations on the percutaneous drug absorption process described herein, we conclude that the percutaneous drug absorption process is better understood by employing two kinetic constants in a mathematical model and that its clinical application would be highly possible.     

Intestinal absorption of amiodarone in man

The jejunal absorption rate of amiodarone and the influence of lipids on it were studied in human volunteers using the intestinal perfusion technique. A nutrient solution (Realmentyl, Sopharga Laboratories, France) with 300 mg of the drug was infused for 120 minutes at the ligament of Treitz. The segment tested was 25 cm long. Two caloric loads of the nutrient solution, 3.3 Kcal/min (solution A) and 1.3 Kcal/min (solution B), A containing total lipid and caloric load 2.5 times higher than B, were administered. Minor interindividual differences in amiodarone absorption rate were observed (20.2 to 31.7%) with solution A. Amiodarone absorption correlated with lipid absorption significantly. Since the maximal plasma concentrations of the drug and the area under the curve (AUC/24 hours) did not correlate with the amount of amiodarone absorbed, the wide fluctuations of amiodarone pharmacokinetics must mainly be due to amiodarone tissue distribution and metabolic pathway.     

Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats

The pacemaker current I_f conducted by hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels plays a critical role in the regulation of cardiac automaticity, with I_f density increased in hypertrophied ventricular myocytes. Amiodarone, a highly effective anti‐arrhythmic agent, blocks human HCN currents and native I_f under normal conditions. To determine the effects of amiodarone under pathological conditions, we monitored I_f under after both acute (0.01, 0.1, 1, 10 and 100 μmol/L) and chronic (10 μmol/L) amiodarone treatment in ventricular myocytes from spontaneously hypertensive rats (SHR) with left ventricular hypertrophy using the whole‐cell patch‐clamp technique. The I_f current density was significantly greater in SHR ventricular myocytes than in cells from healthy normotensive control Wistar‐Kyoto (WKY) rats. Acute application of amiodarone significantly decreased I_f density in myocytes from both SHR and WKY rats. The inhibition was concentration dependent with an IC₅₀ of 4.9 ± 1.2 and 6.9 ± 1.3 μmol/L in myocytes from SHR and WKY rats, respectively. Amiodarone increased the activation and deactivation times of I_f in myocytes from SHR, although it did not alter the relationship of voltage‐dependent activation and the reversal potential of I_f in myocytes from SHR. Chronic exposure of myocytes from SHR to amiodarone potently inhibited I_f and downregulated HCN2 and HCN4, the major channel subtypes underlying native I_f, at both the mRNA and protein level. These findings indicate that amiodarone inhibits I_f under hypertrophied conditions through dual mechanisms: (i) direct channel blockade of I_f currents; and (ii) indirect suppression via negative regulation of HCN channel gene expression. These unique properties of amiodarone may contribute to its anti‐arrhythmic properties under pathological conditions.     

Relationship between lipophilicity and absorption from the liver surface of paraben derivatives and antipyrine in rats

Objectives The importance of drug lipophilicity on absorption from the liver surface was examined in rats using paraben derivatives, antipyrine, Sudan III, and Sudan blue. Methods The log partition coefficient (PC) of n‐octanol/water ranged from ?1.39 to 4.62. The compounds were applied to the rat liver surface using a cylindrical diffusion cell (i.d. 9 mm). Key findings The rate of absorption at 15 min was calculated to be 13.9% for paraben, much lower than that for its derivatives methylparaben, propylparaben and butylparaben (～80%). The obtained first‐order absorption rate constant (k_a) of paraben, methylparaben, propylparaben and antipyrine increased according to lipophilicity. Further lipophilicity resulted in a fall in k_a, implying the importance of affinity for lipids and water in absorption from the liver surface. Thus, a compound with a log PC of around 2.5 is considered to have maximum absorbability from the rat liver surface. A good relationship (r² = 0.97) was recognized between the log k_a and log reciprocal value with the square root of molecular weight of the compounds with a log PC below 2.5. Conclusions The rate of absorption of a drug from the liver surface could be estimated from physicochemical properties such as lipophilicity and molecular weight.     

Clinical pharmacokinetics of amiodarone

Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic activity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily characterised. Specific and sensitive high-pressure liquid chromatographic methods have become available only recently and this partly explains the scarcity of pharmacokinetic data on the drug. Available evidence suggests that absorption of amiodarone following oral administration is erratic and unpredictable; oral bioavailability ranges from 22 to 86%. The drug is eliminated largely by metabolism; less than 1% of the dose is excreted unchanged in the urine. Biliary excretion may have a role in the overall elimination of the drug. Desethyl-amiodarone is the only metabolite positively identified in the plasma of patients receiving treatment with amiodarone; no data are available on its possible pharmacological activity. Since it is a highly lipophilic drug, amiodarone is extensively distributed into tissues. Adipose tissue and skeletal muscle accumulate large amounts of the drug during long term treatment. Myocardium/plasma ratios of amiodarone are high both in man and in animals; peak concentrations in the myocardium are reached within half an hour after administration of an intravenous bolus to dogs. Placental transfer of amiodarone has been demonstrated in humans, while its blood profile is not modified by dialysis treatment. In vitro protein binding of amiodarone has been reported to be 96.3 +/- 0.6%. The plasma half-life of amiodarone after single-dose administration has been reported to be in the range of 3.2 to 79.7 hours. However, after withdrawal of long term amiodarone treatment the half-life is as long as 100 days. Total body clearance ranges from 0.10 to 0.77 L/min after single-dose intravenous administration, and the apparent volume of distribution ranges between 0.9 and 148 L/kg. Amiodarone disposition kinetics in patients with cardiac arrhythmias are not different from those in healthy volunteers. However, the possible effects of liver and cardiac failure on the drug's kinetics have not been studied. Amiodarone potentiates the anticoagulant effect of warfarin, probably by inhibition of its metabolism. Increases of steady-state concentrations of digoxin, together with the appearance of signs of digitalis toxicity, have been reported when amiodarone was given to patients receiving long term treatment with digoxin. Amiodarone has also been shown to interact with other antiarrhythmic agents such as quinidine and procainamide. The time of onset of action of amiodarone after a single intravenous dose ranges between 1 and 30 minutes and its duration of effect between 1 and 3 hours.(ABSTRACT TRUNCATED AT 400 WORDS)     

Modeling Cardiac Uptake and Negative Inotropic Response of Verapamil in Rat Heart: Effect of Amiodarone

Purpose To determine the effect of the P-glycoprotein (Pgp) modulator amiodarone on the pharmacokinetics and pharmacodynamics (PK/PD) of Pgp substrate verapamil in the perfused rat heart.Methods In Langendorff-perfused rat hearts, the outflow concentration–time curve and inotropic response data were measured after a 1.5 nmol dose of [³H]-verapamil (infused within 1 min) in the absence and presence of the amiodarone (1 μM) in perfusate, as well as using a double dosing regimen (0.75 nmol in a 10 min interval). These data were analyzed by a PK/PD model.Results Amiodarone failed to influence the rapid uptake and equilibrium partitioning of verapamil into the heart. The time course of the negative inotropic effect of verapamil, including the ‘rebound’ above the original baseline after the infusion of verapamil was stopped, could be described by a PK/PD tolerance model. Tolerance development (mean delay time, 12 min) led to a reduction in predicted steady-state effect (16%). The EC₅₀ and E _max values as estimated in single dose experiments were 16.4 ± 4.1 nM and 50.5 ± 18.9 mmHg, respectively.Conclusions The result does not support the hypothesis that Pgp inhibition by amiodarone increases cardiac uptake of the Pgp substrate verapamil.     

Bioavailability and disposition kinetics of HI-6 in Beagle dogs

The absorption and disposition kinetics of HI-6 were determined in Beagle dogs given single doses (25 mg kg^?1) of the drug by the intravenous, intramuscular, and oral routes. Concentrations of the oxime in plasma and urine were measured by HPLC. A twocompartment open model was used to describe the disposition curve following intravenous drug administration while a one-compartment open model with first-order absorption adequately described the data following intramuscular or oral administration of the dose. Extravascular distribution of HI-6 was limited (V_ss 203 ml kg^?1) and the drug was eliminated rapidly after intravenous administration (t_1/2 46.5 min, MAT 55.4 min). Systemic clearance was 3.68 ml min^?1 × kg. A major fraction of the dose (63.7 per cent) was excreted in urine over a 24-h collection period. Following intramuscular drug administration, the absorption half-life (t_1/2(a), 5.3 min), MAT (17.1 min), C_max (70.37 μg ml^?1) and t_max (15.9 min) indicate that the drug was rapidly absorbed. Systemic availability was 83.43 per cent after oral drug administration, absorption was preceded by a lag time (23.2 min). The t_1/2(a) (41.5 min), MAT (81.6 min), C_max (4.30 μg ml^?1) and T_max (90.6 min) indicate somewhat delayed absorption. Systemic availability (11.38 per cent) and the fraction of dose excreted unchanged in the urine (9.3 per cent) show that the drug was poorly absorbed. The apparent half-life (58.0 min) and MRT (137.6 min) following oral administration were significantly longer (p <0.05) than following intravenous or intramuscular administration suggesting that the rate of absorption from the gastrointestinal tract decreases the elimination rate of the drug. In conclusion, HI-6 has limited distribution within the body, is rapidly eliminated mainly by renal excretion unchanged in the urine, and the bioavailability (i.e. rate and extent of absorption) of the drug varies with the route of administration.     

The adrenergic antagonism of amiodarone.

Inhibition by amiodarone and propranolol of the chronotropic effect of isoproterenol on spontaneously beating rabbit right atria has been studied in vitro. Propranolol behaved like a typical competitive β₁-adrenoceptor antagonist with a pA₂ value of 8.33. Amiodarone acted as a non-competitive inhibitor with a pD'₂ value of about 4.17. Inhibition by amiodarone and phentolamine of the norepinephrine-induced contractions of isolated rat aortic strips has been studied likewise. Phentolamine was shown to inhibit the adrenergic α receptor competitively with a pA₂ value of 8.69. Amiodarone, though devoid of any appreciable effect on calcium permeability, acted again as a non-competitive inhibitor, with a pD'₂ value of about 4.06. The mechanism of action of amiodarone is discussed.     

The effect of oral dose volume on the absorption of a highly and a poorly water soluble drug in the rat

The influence of dose volume on drug absorption following oral administration of a highly and a poorly water soluble drug was examined in male Sprague-Dawley rats. A constant mass of each ¹⁴C-labeled compound was given via gavage in dose volumes of 1, 5, 10, and 20 mL kg^?1. Blood levels, as well as the quantitative excretion of radioactivity, were measured following each treatment. No significant changes in either the rate or extent of absorption of the water soluble drug were detected. In contrast, the absorption rate of the poorly water soluble drug increased with higher dose volumes, whereas no changes in the extent of absorption were observed. Drug solubility and gastric emptying appeared to be important factors affecting the rate of absorption of the poorly water soluble drug. Since changes in dose volume may affect the absorption characteristics of orally administered compounds, and the extent of such changes may be dependent upon the physicochemical properties of the drug, it is apparent that dose volume is an important experimental variable to be considered in studies comparing absorption data.     

Enhancement of the in Vitro Skin Permeability of Azidothymidine (AZT) via Iontophoresis and Chemical Enhancer

Azidothymidine (AZT) was used as a model drug to study the effect of iontophoresis on the skin permeation of a neutral compound. The rate of in vitro permeation across hairless rat skin was low and highly variable. With iontophoresis treatment the permeation rate was two- to threefold greater than by passive diffusion. The addition of varying amounts of sodium chloride to the donor enhanced the iontophoretic permeation rate an additional two- to threefold possibly due to convective forces. The addition of N-decylmethyl sulfoxide (C₁₀MSO) to the donor increased the permeation rate by several hundred-fold over passive diffusion for hairless rat skin and approximately 75-fold for human skin. No additional enhancement was observed with the combination of C₁₀MSO and iontophoresis treatment at constant current or constant voltage. It may be that the presence of C₁₀MSO lowers the zeta potential of the skin, thus enhancement due to convective flow is minimized.     

Biological activities and pharmacokinetics of aconitine,benzoylaconine, and aconine after oral administration in rats

Aconitine (AC), benzoylaconine (BAC), and aconine (ACN) are three representative alkaloids in Aconitum tubers. Knowing that the drug disposal process in vivo is closely related to the toxicity and efficacy of a drug, it is important to classify the disposal properties of these alkaloids. In this study, the pharmacokinetics of the three alkaloids was investigated. The results showed that the three alkaloids could be quickly absorbed, especially BAC, whose T_max was 0.31 ± 0.17 h. Their C_max was 10.99, 3.99, and 4.29 ng·mL^‐1 respectively, indicating that AC had better absorption than BAC and ACN. Subsequently, we further investigated their absorption mechanism using the Caco‐2 cell monolayer model in vitro. The results showed that they were poorly absorbed, and the absorption of AC and BAC was inhibited by P‐gp, while the absorption of ACN was in a form of passive diffusion. The t_1/2 of AC, BAC and ACN was 1.41, 9.49, and 3.32 h, respectively, indicating that the metabolic or excretion rate of AC was quicker than that of BAC and ACN. Therefore, their metabolic stability was further investigated by using rat liver microsomes in vitro, which showed that AC was easier to be metabolized than BAC and ACN. The excretion experiments showed that AC and ACN were primarily excreted in urine, while BAC was excreted in faeces. In addition, the results of tissue distribution experiments showed that the three alkaloids distributed throughout all the organs, although the distribution rate of AC was slower than that of BAC and ACN. Copyright © 2015 John Wiley & Sons, Ltd.     

Intestinal absorption pathway of γ-aminobutyric acid in rat small intestine

Intestinal absorption of γ-aminobutyric acid (GABA), as a model compound for γ-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of β-alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They show that the intestinal absorption of the γ-aminoacid can be apparently described as a specialized transport mechanism which obeys Michaelis-Menten and first-order kinetics. Parameter values found were V_m = 13.99 ± 2.37 mM h^?1, K_m = 3.87 ± 0.63 mM, and k_a(passive) = 0.362 ± 0.120 h^?1. Through the perfusion of 5 mM β-alanine solutions containing variable concentrations of GABA (from 5 to 50 mM), a partially competitive inhibition of β-alanine absorption was apparently characterized.