Influence of γ‐aminobutyric acid on baclofen intestinal absorption

Nácher, Amparo; Polache, Ana; Moll-Navarro, M J; Plá-Delfina, J.M.; Merino, M.

doi:10.1002/bdd.2510150504

Cited by 7 publications

(10 citation statements)

References 12 publications

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“…6 Bearing this in mind, and since there is a lack of information on GABA intestinal absorption, we have tried to gain an insight into the intestinal absorption mechanisms of this aminoacid, and studied the influence of GABA on /3-alanine intestinal transport, in order to detect possible interactions between these two substances.…”

Section: Introductionmentioning

confidence: 99%

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

Nácher

Polache

Moll-Navarro

et al. 1994

Biopharm & Drug Disp

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Intestinal absorption of gamma-aminobutyric acid (GABA), as a model compound for gamma-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of beta-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 gamma-aminoacid can be apparently described as a specialized transport mechanism which obeys Michaelis-Menten and first-order kinetics. Parameter values found were Vm = 13.99 +/- 2.37 mM h-1, Km = 3.87 +/- 0.63 mM, and ka(passive) = 0.362 +/- 0.120 h-1. Through the perfusion of 5 mM beta-alanine solutions containing variable concentrations of GABA (from 5 to 50 mM), a partially competitive inhibition of beta-alanine absorption was apparently characterized.

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Section: Introductionmentioning

confidence: 99%

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

Nácher

Polache

Moll-Navarro

et al. 1994

Biopharm & Drug Disp

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“…The absorption rate pseudoconstants, k ap , calculated according to eq 1 are also given. According to these results, the baclofen absorption rate pseudoconstant was significantly reduced relative to that found in the presence of 100 mM leucine (k ap ) 0.220 ( 0.050 h -1 ), 7 in the presence of 100 mM taurine (k ap ) 0.561 ( 0.063 h -1 ) and in the presence of 100 mM GABA (k ap ) 0.650 ( 0.010 h -1 ), 31 respectively. This result confirms that more than one carrier system is involved in baclofen absorption.…”

Section: Discussionmentioning

confidence: 66%

“…29,30 We postulated that this carrier could be responsible for the residual absorption seen in the previous studies. 9,31 The k ap obtained show a reduction in baclofen absorption as taurine concentration in the perfusion solution is increased. The one-way ANOVA test shows the existence of significant differences.…”

Section: Discussionmentioning

confidence: 89%

“…31 For this reason, in the final fit (eqs 8 and 9) the V m and K m values (V m ) 11.92 ( 0.7 mM/h, K m ) 8.06 ( 0.5 mM) were fixed to those obtained for baclofen in free solution. 11 According to the results from Table 5, the model of competitive inhibition plus a second component is by far statistically superior.…”

Section: Discussionmentioning

confidence: 99%

“…9 Similar results were obtained when γ-aminobutyric acid (GABA) was selected as inhibitor. 31 In all these inhibition studies we have employed a classical procedure using the Michaelis-Menten equation properly modified when an inhibition phenomenon exists. To perform the fits of the equation to the data, the inhibitor concentration was considered constant.…”

Section: Discussionmentioning

confidence: 99%

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Interaction of Taurine on Baclofen Intestinal Absorption: A Nonlinear Mathematical Treatment using Differential Equations to Describe Kinetic Inhibition Models

Moll-Navarro

Merino

Casabó

et al. 1996

Journal of Pharmaceutical Sciences

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Previous studies showed that the in situ absorption of baclofen in rat jejunum was inhibited by beta-alanine, a nonessential amino acid, and therefore mediated, at least in part, by some beta-amino acid carrier. In this paper a similar study was undertaken using taurine, a sulfonic beta-amino acid, in order to evaluate its effect and to establish a general inhibition model. To achieve this goal, remaining concentrations of inhibitor were also measured and incorporated into the model. Previously, kinetic absorption in situ parameters for taurine in free solution were obtained: Vm = 27.73 +/- 9.99 mM h-1, K(m) = 8.06 +/- 2.82 mM, Ka (passive difussion component) = 0.40 +/- 0.28 h-1. Isotonic solutions containing 0.5 mM baclofen with starting taurine concentrations ranging from 0 to 100 mM were perfused in rat jejunum, and the remaining concentrations of both compounds were measured. The apparent rate pseudoconstant of the drug clearly decreased as the remaining taurine concentration increased. The interaction can be described as a complete competitive inhibition plus a second component, K, noninhibited, K = 0.58 (+/- 0.03) h-1, Ki = 20.62 (+/- 4.04) mM, Vmi = 28.12 (+/- 6.12) mM h-1, Kmi = 11.71 (+/- 2.53) mM, Kai = 0.47 (+/- 0.10) h-1. A residual absorption of baclofen in the presence of high taurine concentrations was observed, which should be attributed to another transport system not associated with the taurine carrier. In order to elucidate whether or not taurine and beta-alanine carriers are two separate entities that baclofen can use for absorption, further experiments using beta-alanine and taurine together as inhibitors (baclofen, 0.5 mM; beta-alanine, 50 mM, and taurine, 50 mM) were developed. Results indicated that baclofen and both amino acids share the same carrier in the intestinal absorption process. We have completed studies using leucine, taurine, and GABA together as inhibitors of drug absorption. An isotonic perfusion solution of 0.5 mM baclofen in the presence of 50 mM leucine, 25 mM taurine, and 25 mM GABA was perfused. Under these conditions the absorption rate pseudoconstant of baclofen decreases until 0.080 h-1 (+/- 0.069). Practical implications of these phenomena are briefly discussed.

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Influence of leucine on intestinal baclofen absorption as a model compound of neutral α‐aminoacids

Cercós-Fortea

Polache

Nácher

et al. 1995

Biopharm & Drug Disp

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The inhibitory effect of the essential alpha-aminoacid L-leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of an in situ rat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5-100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations however did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component, K = 0.35 (+/- 0.08)h-1, Ki = 0.25 (+/- 0.09)mM, AIC = -97.02. In the light of some of the absorption features of the drug, however, the residual absorption of baclofen in the presence of high leucine concentrations should be attributed to another transport system not used by leucine. Apparent parameters characterizing absorption of leucine in the presence of baclofen (0.5 mM) were Vm = 61.02 (+/- 5.46)mM h-1; Km = 8.04 (+/- 0.89)mM, and AIC = -62.25. The results indicate that baclofen and leucine share some carriers in the intestinal absorption processes. Since leucine is an essential dietary aminoacid, and therefore a normal food component, this finding could be relevant in preventing interactions that would lead to a reduced oral bioavailability during baclofen therapy.

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Influence of γ‐aminobutyric acid on baclofen intestinal absorption

Cited by 7 publications

References 12 publications

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

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

Interaction of Taurine on Baclofen Intestinal Absorption: A Nonlinear Mathematical Treatment using Differential Equations to Describe Kinetic Inhibition Models

Influence of leucine on intestinal baclofen absorption as a model compound of neutral α‐aminoacids

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