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

Abstract

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.

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

“…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.…”

“…In our opinion, the second possibility is much more realistic, as is corroborated by the fact that baclofen absorption is better described only by the MichaelisMenten equation. Moreover, recent inhibition studies with neutral R-amino acids 7,8 demonstrated that baclofen could be transported in the rat small intestine using their carrier system, so the existence of a second carrier system not inhibited by taurine is highly probable. Another fact that corroborates the existence of two carrier systems for baclofen absorption is the different values obtained of K mi and K i for taurine (Table 5).…”

“…Over the past 10 years, our previous paper and various others [1][2][3][4][5][6][7][8][9] have clearly demonstrated that some drugs can be transported in the small intestine using the above mentioned carriers. This implies the existence of inhibition phenomena between drugs and nutrients.…”

“…Our previous investigations revealed that baclofen can be transported in the small intestine by the carrier system of neutral amino acids 7,8 and that of -amino acids. 9 We focused the next study on the possible influence of taurine, a -sulfonic amino acid, on the absorption of baclofen.…”

Determination of amino acids by micellar EKC: Recent advances in method development and novel applications to different matrices

“…For instance, quantitation of amino acids in proteins and peptides provides answers as to what protein or protein fragment we have. Measurement in biological fluids of amino acids that can be used to predict the likely course of a disease and to monitor and assist in the management of this disease is a strategy commonly applied for understanding the physiological state of a tissue [1][2][3][4][5][6][7][8][9][10]. Separation of individual amino acid enantiomers is often a critical step in such diverse fields as geological dating [11][12][13][14], food chemistry [6,15], physiology [2,16], and protein/ peptide-based drug development [17].…”