Abstract
Purpose. The purpose of this human intestinal perfusion study was to investigate the transport and metabolism of R/S-verapamil in the human jejunum (in vivo).
Methods. A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut® perfusion tube in 12 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods each of 100 min. The inlet concentrations of verapamil were 4.0 and 40 mg/1 in period one and two, respectively.
Results. The effective jejunal permeability (Peff) of both R- and S-verapamil increased (p < 0.05) when the inlet concentration was increased consistent with saturation of an efflux mechanism. However, both R- and S-verapamil had high intestinal Peff, consistent with complete absorption. The Peff of antipyrine also increased, but there was no difference in the Peff for D-glucose in the two periods. The appearance of R/S-norverapamil in the intestinal perfusate leaving the jejunal segment was non-linear, presumably due to saturation of the CYP3A4 metabolism.
Conclusions. The increased Peff in parallel with increased entering drug concentration is most likely due to saturable efflux by P-glycoprotein(s) in the human intestine.
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REFERENCES
T. Tsuruo, H. Iida, S. Tsukagoshi, and Y. Sakurai. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res. 41:1967-72 (1981).
W. D. Stein. Kinetics of the multidrug transporter (P-glycoprotein) and its reversal. Physiol Rev. 77:545-90 (1997).
M. M. Gottesman and I. Pastan. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385-427 (1993).
C. C. Cordon, J. P. O'Brien, D. Casals, G. L. Rittman, J. L. Biedler, M. R. Melamed, and J. R. Bertino. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA 86:695-8 (1989).
C. C. Cordon, J. P. O'brien, J. Boccia, D. Casals, J. R. Bertino, and M. R. Melamed. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. Journal of Histochemistry and Cytochemistry 38:1277-1288 (1990).
P. Borst, A. H. Schinkel, J. J. Smit, E. Wagenaar, D. L. Van, A. J. Smith, E. W. Eijdems, F. Baas, and G. J. Zaman. Classical and novel forms of multidrug resistance and the physiological functions of P-glycoproteins in mammals. Pharmacol. Ther. 60:289-99 (1993).
A. H. Schinkel et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs, Cell 77:491-502 (1994).
A. H. Schinkel, E. Wagenaar, C. A. Mol, and D. L. van. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517-24 (1996).
A. Sparreboom et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc. Natl. Acad. Sci USA 94:2031-5 (1997).
C. Y. Wu, L. Z. Benet, M. F. Hebert, S. K. Gupta, M. Rowland, D. Y. Gomez, and V. J. Wacher. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin. Pharmacol. Ther. 58:492-7 (1995).
M. F Fromm, D. Busse, H. K. Kroemer, and M. Eichelbaum. Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology 24:796-801 (1996).
P. B. Watkins, S. A. Wrighton, E. G. Schuetz, D. T. Molowa, and P. S. Guzelian. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J. Clin. Invest. 80:1029-36 (1987).
C. G. Regardh, B. Edgar, R. Olsson, M. Kendall, P. Collste, and C. Shansky. Pharmacokinetics of felodipine in patients with liver disease. Eur. J. Clin. Pharmacol. 36:473-9 (1989).
K. E. Thummel, D. O'Shea, M. F. Paine, D. D. Shen, K. L. Kunze, J. D. Perkins, and G. R. Wilkinson. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Pharmacol. Ther. 59:491-502 (1996).
T. Gramatte, R. Oertel, B. Terhaag, and W. Kirch. Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans. Clin. Pharmacol. Ther. 59:541-9 (1996).
U. Wetterich, L. H. Spahn, E. Mutschler, B. Terhaag, W. Rosch, and P. Langguth. Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration-and dose-dependent absorption in vitro and in vivo. Pharm Res. 13:514-22 (1996).
S. Winiwarter, N. Bonman, A. Hallberg, H. Lennernäs, and A. Karlén. Correlation of drug permeability in humans (in vivo) with experimentally and theoretically derived parameters. European Journal of Pharmaceutical Sciences 5/Suppl.2:50 (1997).
U. Fagerholm, M. Johansson, and H. Lennernäs. Comperison between permeability coefficients in rat and human jejunum. Pharm. Res. 13:1336-42 (1996).
L. Knutson, B. Odlind, and R. Hallgren. A new technique for segmental jejunal perfusion in man. Am. J. Gastroenterol. 84:1278-84 (1989).
H. Lennernas, O. Ahrenstedt, R. Hallgren, L. Knutson, M. Ryde, and L. K. Paalzow. Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm. Res. 9:1243-51 (1992).
R. Sandström, A. Karlsson, and H. Lennernäs. Enantioselective analysis of verapamil and norverapamil in intestinal perfusate and plasma (Submitted). J. Chromatogr. (1998).
H. Lennernas, U. Fagerholm, Y. Raab, B. Gerdin, and R. Hallgren. Regional rectal perfusion: a new in vivo approach to study rectal drug absorption in man. Pharm. Res. 12:426-32 (1995).
H. Lennernas, I. D. Lee, U. Fagerholm, and G. L. Amidon. A residence-time distribution analysis of the hydrodynamics within the intestine in man during a regional single-pass perfusion with Loc-I-Gut: in-vivo permeability estimation. J. Pharm. Pharmacol. 49:682-6 (1997).
H. Lennernas, D. Nilsson, S. M. Aquilonius, O. Ahrenstedt, L. Knutson, and L. K. Paalzow. The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man. Br. J. Clin. Pharmacol. 35:243-50 (1993).
H. Lennernas, O. Ahrenstedt, and A. L. Ungell. Intestinal drug absorption during induced net water absorption in man; a mechanistic study using antipyrine, atenolol and enalaprilat. Br. J. Clin. Pharmacol. 37:589-96 (1994).
H. Lennernas. Human jejunal effective permeability and its correlation with preclinical drug absorption models [In Process Citation]. J. Pharm. Pharmacol. 49:627-38 (1997).
H. Lennernas, L. Knutsson, A. Hussain, L. Lesko, T. Salmonson, and G. L. Amidon. The human jejunal Peff-value for each enatiomer of (R,S)-verapamil. Pharm. Res. 13:246 (1996).
R. Sandström, A. Karlsson, and H. Lennernäs. The lack of stereoselective P-glycoprotein mediated transport of R/S-verapamil across the rat jejunum (Submitted). J. Pharm. Pharmacol. (1998).
K. Haussermann, B. Benz, V. Gekeler, K. Schumacher, and M. Eichelbaum. Effects of verapamil enantiomers and major metabolites on the cytotoxicity of vincristine and daunomycin in human lymphoma cell lines. Eur. J. Clin. Pharmacol. 40:53-9 (1991).
G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413-20 (1995).
U. Fagerholm, L. Borgstrom, O. Ahrenstedt, and H. Lennernas. The lack of effect of induced net fluid absorption on the in vivo permeability of terbutaline in the human jejunum. J. Drug. Target. 3:191-200 (1995).
K. S. Lown, D. G. Bailey, R. J. Fontana, S. K. Janardan, C. H. Adair, L. A. Fortlage, M. B. Brown, W. Guo, and P. B. Watkins. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression [see comments]. J. Clin. Invest. 99:2545-53 (1997).
E. G. Schuetz, A. H. Schinkel, M. V. Relling, and J. D. Schuetz. P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc. Natl. Acad. Sci. U S A. 93:4001-5 (1996).
K. S. Lown et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin. Pharmacol. Ther. 62:248-60 (1997).
H. K. Kroemer, H. Echizen, H. Heidemann, and M. Eichelbaum. Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects. J. Pharmacol Exp. Ther. 260:1052-7 (1992).
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Sandström, R., Karlsson, A., Knutson, L. et al. Jejunal Absorption and Metabolism of R/S-Verapamil in Humans. Pharm Res 15, 856–862 (1998). https://doi.org/10.1023/A:1011916329863
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DOI: https://doi.org/10.1023/A:1011916329863