Abstract
Purpose
The objective of this study was to evaluate the in vivo consequences of glycyl-glutamate coadministration on gabapentin oral absorption.
Methods
Rats were administered gabapentin (10 mg/kg plus radiotracer) by gastric gavage, in the absence and presence of dipeptides, and by intravenous administration. Serial blood samples were obtained over 6 h and the pharmacokinetics of gabapentin were determined by noncompartmental analysis.
Results
Glycyl-glutamate coadministration increased the C max of gabapentin by 86% as compared to gabapentin alone. In agreement, the oral absorption of gabapentin, relative to the intravenous dose, was 79% after glycyl-glutamate loading but only 47% when drug was administered alone. However, when glycyl-sarcosine was added to the orally administered admixture of gabapentin plus glycyl-glutamate, values for C max and AUC0–6 h reverted back to that of control. In contrast, the t max and terminal half-life of gabapentin did not change after oral dosing for all treatments.
Conclusions
These findings are unique in demonstrating that under physiologic, in vivo conditions, the luminal presence of glycyl-glutamate could dramatically enhance the Cmax and AUC0–6 h of gabapentin. The results are consistent with previous in situ intestinal perfusion studies in rat, and establish a functional interaction between the activities of PEPT1 and amino acid exchangers.
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Abbreviations
- AUC0–6 h :
-
area under the blood concentration vs. time curve from 0–6 h
- C max :
-
maximal blood concentration
- GB:
-
gabapentin
- GlyGlu:
-
glycyl-glutamate
- GlySar:
-
glycyl-sarcosine
- IV:
-
intravenous dosing
- RIP:
-
rat intestinal perfusion
- SLC:
-
solute carrier family
- T1/2,λz :
-
terminal half-life of drug
- t max :
-
time of maximal blood concentration
References
N. S. Gee, J. P. Brown, V. U. K. Dissanayake, J. Offord, R. Thurlow, and G. N. Woodruff. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha-2-delta subunit of a calcium channel. J. Biol. Chem. 271:5768–5776 (1996).
J. S. Bryans and D. J. Wustrow. 3-Substituted GABA analogs with central nervous system activity: a review. Med. Res. Rev. 19:149–177 (1999).
M. V. Ameringen, C. Mancini, B. Pipe, and M. Bennett. Antiepileptic drugs in the treatment of anxiety disorders: role in therapy. Drugs 64:2199–220 (2004).
B. H. Stewart, A. R. Kugler, P. R. Thompson, and H. N. Bockbrader. 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).
T. Z. Su, E. Lunney, G. Campbell, and D. L. Oxender. Transport of gabapentin, a gamma-amino acid drug, by system L alpha-amino acid transporters: a comparative study in astrocytes, synaptosomes and CHO cells. J. Neurochem. 64:2125–2131 (1995).
M. S. Luer, C. Hamani, M. Dujovny, B. Gidal, M. Cwik, K. Deyo, and J. H. Fischer. Saturable transport of gabapentin at the blood-brain barrier. Neurol. Res. 21:559–562 (1999).
T. V. Nguyen, D. E. Smith, and D. Fleisher. PEPT1 Enhances the uptake of gabapentin via trans-stimulation of b0,+ exchange. Pharm. Res. 24:353–360 (2006).
N. Jezyk, C. Li, B. H. Stewart, X. Wu, H. N. Bockbrader, and D. Fleisher. Transport of pregabalin in rat intestine and Caco-2 monolayers. Pharm. Res. 16:519–526 (1999).
C. M. Stevenson, L. L. Radulovic, H. N. Bockbrader, and D. Fleisher. Contrasting nutrient effects on the plasma levels of an amino acid-like antiepileptic agent from jejunal administration in dogs. J. Pharm. Sci. 86:953–957 (1997).
N. Piyapolrungroj, C. Li, H. Bockbrader, G. Liu, and D. Fleisher. Mucosal uptake of gabapentin (Neurontin) vs. pregabalin in the small intestine. Pharm. Res. 18:1126–1130 (2001).
F. Verrey, E. I. Closs, C. A. Wagner, M. Palacin, H. Endou, and Y. Kanai. CATs and HATs: the SLC7 family of amino acid transporters. Pflugers. Arch. 447:532–42 (2004).
M. Pineda, E. Fernandez, D. Terrents, R. Estevez, C. Lopez, M. Camps, J. Lloberas, A. Zorzano, and M. Palacin. Identification of a membrane protein, LAT-2, that co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J. Biol. Chem. 274:19738–19744 (1999).
Y. Kanai, H. Segawa, K. Miyamoto, H. Uchino, E. Takeda, and H. Endou. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem. 273:23629–23632 (1998).
U. Wenzel, B. Meissner, F. Doring, and H. Daniel. PEPT1-mediated uptake of dipeptides enhances the intestinal absorption of amino acids via transport system b0,+. J. Cell. Physiol. 186:251–259 (2001).
J. Thomson. Sample preparation and counting of biological samples. http://las.perkinelmer.com/content/applicationnotes/an-9002.pdf (accessed 6/4/06). (1999).
Y. S. Kim, W. Birthwhistle, and Y. W. Kim. Peptide hydrolases in the brush border and soluble fractions of small intestinal mucosa of rat and man. J. Clin. Invest. 51:1419–1430 (1972).
V. Ganapathy, M. Brandsch, and F. H. Leibach. Instestinal Transport of Amino Acids and Peptides, Raven Press, New York, 1994.
H. Daniel. Function and molecular structure of brush border membrane peptide/H+ symporters. J. Membr. Biol. 154:197–203 (1996).
D. Pass, and G. Freeth. The rat. ANZCCART News 6:1–4 (1993).
M. L. Hogerle, and D. Winne. Drug absorption by the rat jejunum perfused in situ. Dissociation from the pH-partition theory and role of microclimate-pH and unstirred layer. Naunyn-Schmiedeberg’s Arch. Pharmacol. 322:249–255 (1983).
Y. Shiau, P. Fernandez, M. J. Jackson, and S. McMonagle. Mechanisms maintaining a low pH microclimate in the intestine. Am. J. Physiol. 248:G608–G617 (1985).
L. Salphati, K. Childers, L. Pan, K. Tsutsui, and L. Takahashi. Evaluation of single-pass intestinal-perfusion method in rat for the prediction of absorption in man. J. Pharm. Pharmacol. 53:1007–1013 (2001).
P. G. Welling. Effects of food on drug absorption. Annu. Rev. Nutr. 16:383–415 (1996).
B. E. Gidal, M. M. Maly, J. Buddle, G. L. Lensmeyer, M. E. Pitterle, and Effects of a high-protein meal on gabapentin pharmacokinetics. Epilepsy Res. 23:71–76 (1996).
Acknowledgments
The authors would like to thank Yatsuhiro Tsume for his generous help with the animal studies. This work was supported in part by Grant R01 GM035498 (D.E.S.) from the National Institutes of Health. Theresa V. Nguyen was supported by an American Foundation for Pharmaceutical Education Fellowship, a Pharmacological Sciences Training Program from the National Institutes of Health (Grant T32 GM007767), and by the College
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David Fleisher (deceased) was a co-author of this article.
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Nguyen, T.V., Fleisher, D. & Smith, D.E. In Vivo Effects of Glycyl-Glutamate and Glycyl-Sarcosine on Gabapentin Oral Absorption in Rat. Pharm Res 24, 1538–1543 (2007). https://doi.org/10.1007/s11095-007-9272-x
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DOI: https://doi.org/10.1007/s11095-007-9272-x