INTERACTION OF TAURINE ON BACLOFEN INTESTINAL-ABSORPTION - A NONLINEAR MATHEMATICAL TREATMENT USING DIFFERENTIAL-EQUATIONS TO DESCRIBE KINETIC INHIBITION MODELS

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 sulfon ic beta-amino acid, in order to evaluate its effect and to establish a general inhibition model. To achieve this goal, remaining concentrati ons of inhibitor were also measured and incorporated into the model. P reviously, kinetic absorption in situ parameters for taurine in free s olution were obtained: V-m = 27.73 +/- 9.99 mM h(-1), K-m = 8.06 +/- 2 .82 mM, k(a) (passive difussion component) = 0.40 +/- 0.28 h(-1). Isot onic solutions containing 0.5 mM baclofen with starting taurine concen trations ranging from 0 to 100 mM were perfused in rat jejunum, and th e remaining concentrations of both compounds were measured. The appare nt 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, noninhibi ted, K = 0.58 (+/-0.03) h(-1), K-i = 20.62 (+/-4.04) mM, V-mi = 28.12 (+/-6.12) mM h(-1), K-mi = 11.71 (+/-2.53) mM, k(ai) = 0.47 (+/-0.10) h(-1). A residual absorption of baclofen in the presence of high tauri ne 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 sep arate entities that baclofen can use for absorption, further experimen ts 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 i n the intestinal absorption process. We have completed studies using l eucine, taurine, and GABA together as inhibitors of drug absorption. A n isoionic 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 c onditions the absorption rate pseudoconstant of baclofen decreases unt il 0.080 h(-1) (+/-0.069). Practical implications of these phenomena a re briefly discussed.