Abstract
The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit. Avitriptan capsules were specially formulated with nonradioactive 152 samarium chloride hexahydrate which was neutron-activated to gamma-emitting 153 samarium before dosing. Serial blood samples were collected for analysis of avitriptan up to 24-hr postdose, and serial scintigraphic images were obtained to assess the plasma concentration–time profile in relation to the GI transit of the avitriptan capsule contents. Bioavailability of avitriptan was reduced when administered in the fed condition but only the decrease in AUC(INF) was statistically significant Tmax was significantly delayed between the fed conditions and the fasted condition. Qualitative appearance of plasma concentration–time profiles for avitriptan could be related to the manner in which the drug emptied from the stomach. It was also apparent that avitriptan exerted a secondary pharmacologic effect that temporarily suspended gastric emptying in the fasted treatment. Thus, when gastric emptying was interrupted and then resumed, the net result was a double peak in some of the individual plasma concentration profiles. Scintigraphic analysis also demonstrated that upon emptying from the stomach, avitriptan was rapidly absorbed from the upper small intestine. In the fed state, gastric emptying was slow and continuous resulting in extended absorption and a lower occurrence of double peaks. Qualitatively, the intrasubject variability in Cmax and AUC could be explained by the intrasubject variability in gastric emptying in both fasted and fed conditions.
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REFERENCES
R. A. Myers, N. S. Sarbin, M. A. Kapin, and F. D. Yocca. Modulation of feline cephalic arterio-venous shunting and systemic hemodynamics following administration of BMS-180048 and sumatriptan. FASEB J. Abstr. 9:A23 (1995).
F. D. Yocca, J. A. Gylys, J. Buchanan, and R. A. Myers. Effect of BMS-180048 on carotid arterial blood flow and arteriovenous blood oxygen content in the anesthetized dog. FASEB J. Abstr. 9:A23 (1995).
H. L. Wiener, G. P. Thalody, and F. D. Yocca. Kinetic characterization of the responses to BMS-180048, A novel antimigraine agent in cerebral blood vessels. FASEB J. Abstr. 9:A347 (1995).
N. S. Sarbin, J. A. Gylys, L. G. Iben, C. D. Mahle, D. G. Izzarelli, E. M. Parker, J. W. Noonan, A. D. Williams, D. W. Smith, E. Hamel, and F. D. Yocca. The receptor binding and vascular in vitro pharmacological profile of BMS-180048. FASEB J. Abstr. 9:A347 (1995).
P. H. Marathe, D. S. Greene, and R. H. Barbhaiya. Disposition of [14C]avitriptan in the rat and man. Drug Metab. Dispos. 25:881–888 (1997).
P. H. Marathe, D. S. Greene, J. S. Lee, and R. H. Barbhaiya. Assessment of effect of food, gender and intra-subject variability in the pharmacokinetics of avitriptan. Biopharm. Drug Dispos. 19:153–157 (1998).
P. H. Marathe, D. S. Greene, G. D. Kolli, and R. H. Barbhaiya. Evaluation of the effect of food on the pharmacokinetics of avitriptan. Biopharm. Drug Dispos. (in press).
G. A. Digenis and E. P. Sandefer. Gamma scintigraphy and neutron activation techniques in the in vivo assessment of orally administered dosage forms. Crit. Rev. Ther. Drug Carrier Syst. 7:309–345 (1991).
S. S. Davis, J. G. Hardy, S. P. Newman, and I. R. Wilding. Gamma scintigraphy in the evaluation of pharmaceutical dosage forms. Eur. J. Nucl. Med. 19:971–986 (1992).
G. A. Digenis, E. P. Sandefer, A. F. Parr, R. M. Beihn, C. McClain, B. M. Scheinthal, I. Ghebre-Sellassie, U. Iyer, R. U. Nesbitt, and E. Randinitis, Gastrointestinal behavior of orally administered radiolabeled erythromycin pellets in man as determined by gamma scintigraphy. J. Clin. Pharmacol. 30:621–631 (1990).
C. G. Wilson, G. D. Parr, J. W. Kennerly, M. J. Taylor, S. S. Davis, J. G. Hardy, and J. A. Rees. Pharmacokinetics and in vivo scintigraphic monitoring of a sustained release acetylsalicylic acid formulation. Int. J. Pharm. 18:1–8 (1984).
J. N. C. Healey. Gastrointestinal transit and release of mesalazine tablet in patients with inflammatory bowel disease. Scand. J. Gastroenterol. 25(suppl. 172):47–51 (1990).
J. G. Hardy, W. J. Harvey, R. A. Sparrow, G. B. Marshall, K. P. Steed, M. Macarios, and I. R. Wilding. Localization of drug release from an oral sustained-release formulation of 5-ASA (Pentasa) in the gastrointestinal tract using gamma scintigraphy. J. Clin. Pharmacol. 33:712–718 (1993).
C. G. Wilson, N. Washington, J. G. Hardy, and S. W. Bond. The influence of food on the absorption of acyclovir: A pharmacokinetic and scintigraphic assessment. Int J. Pharm. 38:221–225 (1987).
J. M. Price, S. S. Davis, R. A. Sparrow, and I. R. Wilding. The effect of meal composition on the gastrocolonic response: Implications for drug delivery to the colon. Pharm. Res. 10:722–726 (1993).
P. Grenier, G. Vergnault, E. P. Sandefer, W. J. Doll, R. C. Page, and G. A. Digenis. In vivo evaluation of a multi-layered tablet by gamma scintigraphy followed a low fat and high fat meal. Pharm. Res. 13:S–282 (1996).
J. R. Crison, P. R. Siersma, G. L. Amidon, E. P. Sandefer, W. J. Doll, R. C. Page, and G. A. Digenis. Scintigraphic comparison of the fed and fasted state on the delivery and GI transit of a time-released dosage form. Pharm. Res. 13:S–321 (1996).
A. F. Parr, M. Jay, G. A. Digenis, and R. N. Beihn. Radiolabeling of intact tablets by neutron activation for in vivo scintigraphic studies. J. Pharm. Sci. 74:590–591 (1985).
G. A. Digenis, E. P. Sandefer, R. M. Beihn, and A. F. Parr. Dual-Isotope imaging of neutron activated erbium-171 and samarium-153 and the in vivo evaluation of a duallabeled bilayer tablet by gamma scintigraphy. Pharm. Res. 8:1335–1340 (1991).
E. Brewer, E. Bennet, M. Letham, J. Henion, and P. H. Marathe. Quantitative determination of BMS-180048, BMS-184273, BMS-203518 and BMY-41728 in plasma using ion spray LC/MS/MS. Pharm. Res. 13:S–63 (1996).
M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982.
R. C. Littel, R. J. Freund, and P. S. Spector. SAS System for Linear Models, 3rd ed., SAS Institute, Inc., Cary, NC, 1991.
J. X. Sun, B. Walter, E. P. Sandefer, R. C. Page, G. A. Digenis, U. Y. Ryo, A. Cipriano, W. M. Maniara, M. L. Powell, and K. Chan. Explaining variable absorption of a hypolipidemic agent (CGP 43371) in healthy subjects by gamma scintigraphy and pharmacokinetics. J. Clin. Pharmacol. 36:230–237 (1996).
L. A. Houghton, P. Fowler, O. N. Keene, and N. W. Read. Effect of sumatriptan, a new 5HT1-like agonist, on liquid gastric emptying in man. Aliment. Pharmacol. Ther. 6:685–691 (1992).
J. W. Lance. 5HT1-like receptor agonist as a novel approach to the treatment of acute migraine: General discussion. Cephalalgia 9:97–101 (1989).
E. P. Sandefer. Contributions of gamma scintigraphy to the in vivo evaluation of oral dosage forms: Implications of gastrointestinal transit times and the effect on drug absorption. Dissertation, University of Kentucky, Lexington, 1996, p. 223.
A. B. Suttle, G. M. Pollack, and K. L. Brouwer. Use of a pharmacokinetic model incorporating discontinuous gastrointestinal absorption to examine the occurrence of double peaks in oral concentration-time profiles. Pharm. Res. 9:350–356 (1992).
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Marathe, P.H., Sandefer, E.P., Kollia, G.E. et al. In Vivo Evaluation of the Absorption and Gastrointestinal Transit of Avitriptan in Fed and Fasted Subjects Using Gamma Scintigraphy. J Pharmacokinet Pharmacodyn 26, 1–20 (1998). https://doi.org/10.1023/A:1023236823320
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DOI: https://doi.org/10.1023/A:1023236823320