Abstract
Sublingual administration of certain buffered propranolol may improve the rate and extent of absorption compared to oral administration. The main objectives of this study were to (1) compare the plasma propranolol concentrations (Cp-prop) following sublingual administration of a specially buffered formulation (Promptol™) to that following oral administration of Inderal® and (2) evaluate the utility of a special pharmacokinetic model in describing the Cp-prop following sublingual administration. Eighteen healthy volunteers received 10 mg sublingual Promptol™ or oral Inderal®. Multiple Cp-prop were determined and their pharmacokinetics compared. Additional data following sublingual 40 mg Promptol™ or Inderal® were utilized for evaluation of a special advanced compartmental absorption and transit (ACAT) model. For model simulation, the physicochemical parameters were imported from AMET predictor, whereas the pharmacokinetic parameters were calculated and optimized by Gastroplus®. Based on this model, the quantity of drug absorbed via buccal/sublingual mucosa was estimated. Cp-prop was higher at earlier times with 3-fold greater relative bioavailability following sublingual Promptol™ compared to that from oral Inderal®. The special ACAT model provided excellent goodness of fit of Cp-prop-time curve and estimated a 56.6% increase in absorption rate from Promptol™ and higher initial Cp-prop compared to the regular formulation. The modified ACAT model provided a useful approach to describe sublingual absorption of propranolol and clearly demonstrated an improvement of absorption of Promptol™. The sublingual 10 mg Promptol™ achieved not only a similar systemic exposure as 30 mg oral Inderal® but an earlier effective Cp-prop which may be advantageous for certain clinical conditions.
Similar content being viewed by others
References
Frishman WH. β-Adrenoceptor antagonists: new drugs and new indications. New Engl J Med. 1981;305(9):500–6. doi:10.1056/NEJM198108273050907.
Angrini M, Leslie JC, Shephard RA. Effects of propranolol, buspirone, pCPA, reserpine, and chlordiazepoxide on open-field behavior. Pharmacol Biochem Behav. 1998;59(2):387–97. doi:10.1016/s0091-3057(97)00457-7.
Fourneret P, Desombre H, de Villard R, Revol O. Interest of propranolol in the treatment of school refusal anxiety: about three clinical observations. Encephale. 2001;27(6):578–84.
Gruber RP, Roberts C, Schooler W, Pitman RK. Preventing postsurgical dissatisfaction syndrome after rhinoplasty with propranolol: a pilot study. Plast Reconstr Surg. 2009;123(3):1072–8. doi:10.1097/PRS.0b013e318199f63f.
Mazzuero G, Galdangelo F, Zotti AM, Bertolotti G, Tavazzi L. Effects of propranolol, atenolol, and chlordesmethyldiazepam on response to mental stress in patients with recent myocardial infarction. Clin Cardiol. 1987;10(6):293–302.
Mealy K, Ngeh N, Gillen P, Fitzpatrick G, Keane FB, Tanner A. Propranolol reduces the anxiety associated with day case surgery. Eur J Surg. 1996;162(1):11–4.
Taylor F, Cahill L. Propranolol for reemergent posttraumatic stress disorder following an event of retraumatization: a case study. J Trauma Stress. 2002;15(5):433–7. doi:10.1023/a:1020145610914.
Vaiva G, Ducrocq F, Jezequel K, Averland B, Lestavel P, Brunet A, et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry. 2003;54(9):947–9. doi:10.1016/s0006-3223(03)00412-8.
Mathias NR, Hussain MA. Non-invasive systemic drug delivery: developability considerations for alternate routes of administration. J Pharm Sci. 2010;99(1):1–20. doi:10.1002/jps.21793.
Squier CA, Hall BK. In-vitro permeability of porcine oral mucosa after epithelial separation, stripping and hydration. Arch Oral Biol. 1985;30(6):485–91.
Duchateau GSMJE, Zuidema J, Merkus FWHM. Bioavailability of propranolol after oral, sublingual, and intranasal administration. Pharm Res. 1986;3(2):108–11.
Chow M, Zuo JZ, Wang Y. Method of enhancing absorptions of transmucosal administration formulations. USA patent, 2008: US7329416.
Wang Y, Zuo Z, Chen X, Tomlinson B, Chow MSS. Improving sublingual delivery of weak base compounds using pHmax concept: application to propranolol. Eur J Pharm Sci. 2010;39(4):272–8. doi:10.1016/j.ejps.2009.12.011.
Huang W, Lee SL, Yu LX. Mechanistic approaches to predicting oral drug absorption. AAPS J. 2009;11(2):217–24. doi:10.1208/s12248-009-9098-z.
Lukacova V, Woltosz W, Bolger M. Prediction of modified release pharmacokinetics and pharmacodynamics from < b > <i > in vitro </b > immediate release, and intravenous data. AAPS J. 2009;11(2):323–34. doi:10.1208/s12248-009-9107-2.
Bolger M, Lukacova V, Woltosz W. Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine. AAPS J. 2009;11(2):353–63. doi:10.1208/s12248-009-9111-6.
Olanoff LS, Walle T, Cowart TD, Walle UK, Oexmann MJ, Conradi EC. Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis. Clin Pharmacol Ther. 1986;40(4):408–14.
Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics & pharmacokinetics, 5th edn. New York: McGraw-Hill Medical Publishing Division; 2004.
Boxenbaum HG, Riegelman S, Elashoff RM. Statistical estimations in pharmacokinetics. J Pharmacokinet Biopharm. 1974;2(2):123–48.
Kates RE. Absorption kinetics of sublingually administered propranolol. J Med. 1977;8(6):393–402.
Henry JA, Ohashi K, Wadsworth J, Turner P. Drug recovery following buccal absorption of propranolol. Br J Clin Pharmacol. 1980;10(1):61–5.
Gomeni R, Bianchetti G, Sega R, Morselli PL. Pharmacokinetics of propranolol in normal healthy volunteers. J Pharmacokinet Biopharm. 1977;5(3):183–92.
Bruce TJ, Saeed SA. Social anxiety disorder: a common, underrecognized mental disorder. Am Fam Physician. 1999;60(8):2311–20. 22.
Pine M, Favrot L, Smith S, McDonald K, Chidsey CA. Correlation of plasma propranolol concentration with therapeutic response in patients with angina pectoris. Circulation. 1975;52(5):886–93. doi:10.1161/01.cir.52.5.886.
AHFS Drug Information. Bethesda, MD Authority of the Board of the American Society of Health-system Pharmacists; American Hospital Formulary Service; 2012.
Julius S, Pascual AV, London R. Role of parasympathetic inhibition in the hyperkinetic type of borderline hypertension. Circulation. 1971;44(3):413–8. doi:10.1161/01.cir.44.3.413.
Weiss YA, Safar ME, Chevillard C, Frydman A, Simon A, Lemaire P, et al. Comparison of the pharmacokinetics of intravenous dl-propranolol in borderline and permanent hypertension. Eur J Clin Pharmacol. 1976;10(6):387–93.
Mansur Ade P, Ramires JA, Avakian SD, de Paula RS, Pileggi F. [Comparison of the effects of diazepam, nifedipine, propranolol and a combination of nifedipine and propranolol, by sublingual administration, in patients with hypertensive crisis]. Arq Bras Cardiol. 1991;57(4):313–7.
Johnston GD. Dose–response relationships with antihypertensive drugs. Pharmacol Therapeut. 1992;55(1):53–93. doi:10.1016/0163-7258(92)90029-y.
Acknowledgments
This study was supported by an external grant from Comprehensive Drug Enterprises Ltd., Hong Kong Science Park, Hong Kong.
Conflict of Interest
Yanfeng Wang and Benjamin T.K. Lee are employees of the company, and Moses S.S. Chow is a shareholder of the company.
Author information
Authors and Affiliations
Corresponding author
Additional information
Yanfeng Wang and Zhijun Wang contributed equally to this work.
Rights and permissions
About this article
Cite this article
Wang, Y., Wang, Z., Zuo, Z. et al. Clinical Pharmacokinetics of Buffered Propranolol Sublingual Tablet (Promptol™)—Application of a New “Physiologically Based” Model to Assess Absorption and Disposition. AAPS J 15, 787–796 (2013). https://doi.org/10.1208/s12248-013-9479-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12248-013-9479-1