Abstract
Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is not alpha to the carboxylate functionality. Gabapentin is not metabolized by humans, and thus, the amount of gabapentin excreted by the renal route represents the fraction of dose absorbed. Clinical trials have reported dose-dependent bioavailabilities ranging from 73.8 ± 18.3 to 35.7 ± 18.3% when the dose was increased from 100 to 1600 mg. The permeability of gabapentin in the rat intestinal perfusion system was consistent with carrier-mediated absorption, i.e., a 75 to 80% decrease in permeability when the drug concentration was increased from 0.01 to 50 mM (0.46 ± 0.05 to 0.12 ± 0.04). Excellent agreement was obtained between the actual clinical values and the predicted values from in situ results for the fraction of dose absorbed calculated using the theoretically derived correlation, F abs = 1 - exp(−2P eff) by Ami-don et al. (Pharm. Res. 5:651–654, 1988). The permeability values obtained for gabapentin correspond to 67.4 and 30.2% of the dose absorbed at the low and high concentrations, respectively. In the everted rat intestinal ring system, gabapentin shared an inhibition profile similar to that of L-phenylalanine. Characteristics of gabapentin uptake included cross-inhibition with L-Phe, sensitivity to inhibition by L-Leu, stereoselectivity as evidenced by incomplete inhibition by D-Phe, and lack of effect by Gly. Our findings support absorption of gabapentin by a saturable pathway, system L, shared by the large hydrophobic amino acids, L-Phe and L-Leu. The saturable absorption pathway makes a major contribution to the lack of proportionality in plasma levels of drug with increasing dose ob-served in the clinic.
Similar content being viewed by others
REFERENCES
B. Schmidt. Potential antiepileptic drugs: Gabapentin. In R. Levy, R. Mattson, B. Meldrum, J. K. Penry, and E. Dreifuss (eds.), Antiepileptic Drugs, Raven Press, New York, 1989, pp. 925–935.
G. D. Bartoszyk, N. Meyerson, W. Reimann, G. Satzinger, and A. von Hodenberg. Gabapentin. In B. S. Meldrum and R. J. Porter (eds.), New Anticonvulsant Drugs, John Libbey, London, 1986, pp. 147–163.
N. Suman-Chauhan, D. R. Hill, and G. N. Woodruff. 3H-Gabapentin binds to a novel site in rat cortical synaptic plasma membranes. Br. J. Pharmacol. 104 (Suppl):71P (1991).
K.-O. Vollmer, A. von Hodenberg, and E. U. Kolle. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneim.-Forsch./Drug Res. 36:830–839 (1986).
K.-O. Vollmer, H. Anhut, P. Thomann, F. Wagner, and D. Jahnchen. Pharmacokinetic model and absolute bioavailability of the new anticonvulsant gabapentin. In J. Manelis (ed.), Advances in Epileptology Series, Vol. 17, Raven Press, New York, 1989, pp. 209–211.
H. N. Christensen. Role of amino acid transport and counter-transport in nutrition and metabolism. Physiol. Rev. 70:43–77 (1990).
G. L. Amidon, P. J. Sinko, and D. Fleisher. Estimating human oral fraction dose absorbed: A correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm. Res. 5:651–654 (1988).
D. Fleisher, N. Sheth, H. Griffin, M. McFadden, and G. Aspacher. Nutrient influences on rat intestinal phenytoin uptake. Pharm. Res. 6:332–337 (1989).
B. H. Stewart, G. L. Amidon, and R. K. Brabec. Uptake of prodrugs by rat intestinal mucosal cells: Mechanism and pharmaceutical implications. J. Pharm. Sci. 75:940–945 (1986).
R. B. Fisher and D. S. Parsons. The gradient of mucosal surface area in the small intestine of the rat. J. Anat. 84:272–282 (1950).
B. H. Stewart, A. R. Kugler, P. R. Thompson, and H. N. Bockbrader. Elucidation of the intestinal absorption mechanism of gabapentin using in situ and in vitro methodology in the rat. Pharm. Res. 8:S200 (1991).
H. H. Maurer and A. F. E. Rump. Intestinal absorption of gabapentin in rats. Arzneim.-Forsch./Drug Res. 41(I):104–106 (1991).
M. Gibaldi and B. Grundhofer. Drug transport VI: Functional integrity of the rat everted small intestine with respect to passive transfer. J. Pharm. Sci. 61:116–119 (1972).
O. Satoh, Y. Kudo, H. Shikata, K. Yamada, and T. Kawasaki. Characterization of amino-acid transport systems in guinea-pig intestinal brush-border membrane. Biochim. Biophys. Acta 985:120–126 (1989).
B. R. Stevens, H. J. Ross, and E. M. Wright. Multiple transport pathways for neutral amino acids in rabbit jejunal brush border vesicles. J. Membr. Biol. 66:213–223 (1982).
M. Hu, P. J. Sinko, A. L. J. DeMeere, D. A. Johnson, and G. L. Amidon. Membrane permeability parameters for some amino acids and β-lactam antibiotics: Application of the boundary layer approach. J. theor. Biol. 131:107–114 (1988).
M. Hu and R. T. Borchardt. Mechanism of transcellular transport of L-phenylalanine in an intestinal epithelial model system (CACO-2). I. Apical uptake of phenylalanine. Pharm. Res. 7:S156 (1990).
D. M. Matthews, R. H. Gandy, E. Taylor, and D. Burston. Influx of two dipeptides, glycylsarcosine and L-glutamyl-L-glutamic acid, into hamster jejunum in vitro. Clin. Sci. 56:15–23 (1979).
B. H. Stewart, S. A. Dando, and R. A. Morrison. In vitro uptake of SQ 29,852 by everted rat intestinal rings. Pharm. Res. 7(9):S156 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stewart, B.H., Kugler, A.R., Thompson, P.R. et al. A Saturable Transport Mechanism in the Intestinal Absorption of Gabapentin Is the Underlying Cause of the Lack of Proportionality Between Increasing Dose and Drug Levels in Plasma. Pharm Res 10, 276–281 (1993). https://doi.org/10.1023/A:1018951214146
Issue Date:
DOI: https://doi.org/10.1023/A:1018951214146