Abstract
Purpose. To determine the apparent bidirectional permeabilities of gabapentin (GBP) across the blood-brain barrier (BBB) using a novel microdialysis-pharmacokinetic approach.
Methods. Rats were administered intravenous infusions of [14C]GBP to achieve clinically relevant steady-state plasma concentrations. Microdialysis was used to monitor GBP concentration in brain extracellular fluid (ECF) in conscious animals. Brain tissue GBP concentration was measured at termination. The BBB influx (CL1) and efflux (CL2) permeabilities of GBP were estimated with a hybrid pharmacokinetic model assuming that transport between intra-and extracellular space was more rapid than transport across the BBB. The time course of GBP concentration in brain tissue was determined independently to validate the model assumption.
Results and Conclusions. Simulations of the concentration-time course of GBP in brain tissue based on this modeling correlated well with the time-course of brain tissue concentrations determined after intravenous bolus administration and validated this pharmacokinetic-microdialysis approach for estimation of BBB permeabilities. The values for CL1 and CL2 were 0.042 (0.017) and 0.36 (0.16) ml/min·g-brain, respectively, indicating that GBP was more efficiently transported from brain ECF to plasma. The total brain tissue concentration of GBP was significantly higher than the ECF concentration at steady-state due to intracellular accumulation and tissue binding, that if not considered, will lead to underestimated efflux BBB permeability using the tissue homogenate-pharmacokinetic approach.
Similar content being viewed by others
REFERENCES
J. Kehr. A survey on quantitative microdialysis: theoretical models and practical implications. J. Neurosci. Methods 48:251–261 (1993).
Y. Wang, S. L. Wong, and R. J. Sawchuk. Microdialysis calibration using retrodialysis and zero-net flux: Application to a study of the distribution of zidovudine to rabbit CSF and thalamus. Pharm. Res. 10, 1411–1419 (1993).
Y. Wang and R. J. Sawchuk. Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion. J. Pharm. Sci. 84:871–876 (1995).
Y. Takasato, S. I. Rapoport, Q. R. Smith. An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am. J. Physiol. 16:H484–H493 (1984).
H. Benveniste and P. C. Huttemeier. Microdialysis: Theory and application. Progress in Neurobiology. 35:195–215 (1990).
D. F. Welty, G. P. Schielke, M. G. Vartanian, C. P. Taylor. Gabapentin anticonvulsant action in rats: disequilibrium with peak drug concentrations in plasma and brain microdialysate. Epilepsy Res. 16:175–181 (1993).
L. L. Radulovic, D. Turck, A. Von Hodenberg, K.-O. Vollmer, W. P. McNally, P. D. Dehart, B. J. Hanson, H. N. Bockbrader, and T. Chang. Disposition of gabapentin (Neurontin) in mice, rats, dogs, and monkeys. Drug Met. Disp. 23:441–448 (1995).
Rosenberg, G. A. Brain Fluids and Metabolism, Oxford University Press, New York, NY, 1990, pp. 15–53.
B. K. Malhotra, M. Lemaire, and R. J. Sawchuk. Investigation of the distribution of EAB 515 to cortical ECF and CSF in freely moving rats utilizing microdialysis. Pharm. Res. 11:1223–1232 (1994).
C. I. Larsson. The use of an ‘internal standard’ for control of recovery in microdialysis. Life Sci. 49:73–78 (1991).
D. Scheller and J. Kolb. The internal reference technique in microdialysis: A practical approach to monitoring dialysis efficiency and calculating tissue concentration from dialysate samples. J. Neurosci. Methods 40:31–48 (1991).
E. Ben-Menachem, L. I. Persson and T. Hedner. Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin. Epilepsy Res. 11:45–49 (1992).
M. Bradbury. The Concept of a Blood-Brain Barrier, John Wiley & Sons, New York, 1979, pp 120.
D. O. Cooney. Biomedical Engineering Principles, Marcel Dekker, Inc., New York, 1976.
K. H. Dykstra, A. Arya, D. M. Arriola, P. M. Bungay, P. F. Morrison, and R. L. Dedrick. Microdialysis study of zidovudine (AZT) transport in rat brain. J. Pharmacol. Exp. Therap. 267:1227–1236 (1993).
W. M. Pardridge. Brain drug delivery and blood-brain barrier transport. Drug Delivery. 1:83–101 (1993).
T.-Z. Su, E. Lunney, G. Campbell, and D. L. Oxender. Transport of gabapentin, a γ-amino acid drug, by system L α-amino acid transporters: a comparative study in astrocytes, synaptosomes and CHO cells. J. Neurochem. 64:2125–2131 (1995).
H. F. Cserr and C. S. Patlak. Secretion and bulk flow of interstitial fluid. In M. W. B. Bradbury (eds.), Physiology and Pharmacology of the Blood-Brain Barrier, Springer-Verlag, New York, NY, 1993, pp. 246–253.
M. B. Segal and B. V. Zlokovic. The Blood-Brain Barrier, Amino Acids and Peptides. Kluwer Academic Publishers, Boston, 1990, pp 37.
G. D. Bartoszyk, N. Meyerson, W. Reimann, G. Satzinger., A. Von Hodenberg. In: Current Problems in Epilepsy, vol. 4, Anticonvulsant Drugs, Eds. Meldrum B.S., Porter R. J., London, John Libbey 1986, 147–163.
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).
H. Davson, B. Zlokovic, L. Rakic, and M. B. Segal. An Introduction to the Blood-Brain Barrier. CRC Press, Inc., Ann Arbor, 1993, p. 174.
D. C. Markovitz and J. D. Fernstrom. Diet and uptake of aldomet by the brain: competition with natural large neutral amino acids. Science 197:1014–1015(1977).
A. L. Betz and G. W. Goldstein. Polarity of the blood-brain barrier: neutral amino acid transport into isolated brain capillaries. Science, 202:225–226 (1978).
R. J. Thurlow, J. P. Brown, N. S. Gee, D. R. Hill, and G. N. Woodruff. [3H]gabapentin may label a system-L-like neutral amino acid carrier in brain. Eur. J. Pharmacol., Mol. Pharmacol. 247:341–345 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wang, Y., Welty, D.R. The Simultaneous Estimation of the Influx and Efflux Blood-Brain Barrier Permeabilities of Gabapentin Using a Microdialysis-Pharmacokinetic Approach. Pharm Res 13, 398–403 (1996). https://doi.org/10.1023/A:1016092525901
Issue Date:
DOI: https://doi.org/10.1023/A:1016092525901