Pharmacokinetics and pharmacodynamics (PK/PD) of irbesartan in Beagle dogs after oral administration at two dose rates

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Irbesartan (Irb) is an angiotensin II type 1 receptor antagonist widely used in humans to treat hypertension. Age-related diseases such as hypertension are increasingly being diagnosed in dogs and there is the need for new drugs. The PK/PD of Irb was tested in Beagle dogs. Ten healthy Beagles were orally administered two dose rates (2 and 5 mg/kg), according to a cross over study design. Blood collections for PK analysis and systolic blood pressure (SBP), heart and respiratory rate, mucous membranes colour, capillary refill time and temperature evaluations were performed at scheduled intervals. The drug plasma concentration was dose dependent. The dogs administered 5 mg/kg showed a significant reduction in SBP, while in those receiving 2 mg/kg, this parameter was minimally affected. A counter clockwise hysteresis showed no direct correlation between SBP and plasma concentrations. The minimum effective concentration was theorized to be within the range 550-800 ng/mL. Although further studies are necessary, 5 mg/kg seems to be the more appropriate dose to obtain a hypotensive effect in Beagle dogs.

Awan NA, Mason DT (1996) Direct selective blockade of the vascular angiotensin II receptors in therapy for hypertension and severe congestive heart failure. Am Heart J 131: 177-185.

Borghi C, Cicero AF (2012) The role of irbesartan in the treatment of patients with hypertension: a comprehensive and practical review. High Blood Press Cardiovasc Prev 19: 19-31.

Borobia AM, Novalbos J, Guerra-López P, López-Rodr´ıguez R, Tabares B, Rodr´ıguez V, Abad-Santos F, Carcas AJ (2009) Influence of sex and CYP2D6 genotype on mirtazapine disposition, evaluated in Spanish healthy volunteers. Pharmacol Res 59: 393-398.

Bramlage P, Durand-Zaleski I, Desai N, Pirk O, Hacker C (2009) The value of irbesartan in the management of hypertension. Expert Opin Pharmacother 10: 1817-1831.

Croom KF, Plosker GL (2008) Irbesartan: a review of its use in hypertension and diabetic nephropathy. Drugs 68: 1543-1569.

Derendorf H, Lesko LJ, Chaikin P, Colburn WA, Lee P, Miller R, Powell R, Rhodes G, Stanski D, Venitz J (2000) Pharmacokinetic/pharmacodynamic modeling in drug research and development. J Clin Pharmacol 40: 1399-1418.

Fassler PE, Tranquilli WJ, Paul AJ, Soll MD, DiPietro JA, Todd KS (1991) Evaluation of the safety of ivermectin administered in a beef-based formulation to ivermectin- sensitive Collies. J Am Vet Med Assoc 199: 457-460.

Gabrielsson J, Weiner D (2002) Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications, Swedish Pharmaceutical Press, Stockholm, Sweden.

German AJ (2006) The growing problem of obesity in dogs and cats. J Nutr 136: 1940s-1946s.

Giorgi M (2012) Tramadol vs tapentadol: A new horizon in pain treatment? Am J Anim Vet Sci 7: 7-11.

Giorgi M, Meizler A, Mills PC (2012) Pharmacokinetics of the novel atypical opioid tapentadol following oral and intravenous administration in dogs. Vet J 194: 309-313.

Giorgi M, Owen H (2012a) Flupirtine: a human drug with potential for use in the veterinary field. Am J Anim Vet Sci 7: 213-217.

Giorgi M, Owen H (2012b) Mirtazapine in veterinary medicine a pharmacological rationale for its application in chronic pain. Am J Anim Vet Sci 7: 42-47.

Giorgi M, Portela DA, Breghi G, Briganti A (2012) Pharmacokinetics and pharmacodynamics of zolpidem after oral administration of a single dose in dogs. Am J Vet Res 73: 1650-1656.

Giorgi M, Saccomanni G, Lebkowska-Wieruszewska B, Kowalski C (2009) Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study. Vet J 180: 253-255.

Hallberg P, Karlsson J, Lind L, Michae¨lsson K, Kurland L, Kahan T, Malmqvist K, Ohman KP, Nystro¨m F, Liljedahl U, Syva¨nen AC, Melhus H (2004) Gender-specific association between preproendothelin-1 genotype and reduction of systolic blood pressure during antihypertensive treatment-results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA). Clin Cardiol 27: 287-290.

Hoffman J, Perkins C (2008) Veterinary generics: an enigma among niche markets. J Gen Med 5: 281-289.

Huang XH, Qiu FR, Xie HT, Li J (2005a) Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive dogs. J Cardiovasc Pharmacol 46: 863-869.

Huang XH, Qiu FR, Xie HT, Li J (2005b) Pharmacokinetic and pharmacodynamic of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions. Eur J Drug Metab Pharmacokinet 30: 121-126.

Ilkiw JE, Ratcliffe RC (1987) Paracetamol toxicity in a cat. Aust Vet J 64: 245-247.

Lam CS, Carson PE, Anand IS, Rector TS, Kuskowski M, Komajda M, McKelvie RS, McMurray JJ, Zile MR, Massie BM, Kitzman DW (2012) Sex differences in clinical characteristics and outcomes in elderly patients with heart failure and preserved ejection fraction: the irbesartan in heart failure with preserved ejection fraction (I-PRESERVE) trial. Circ Heart Fail 5: 571-578.

Marino MR, Vachharajani NN (2002) Pharmacokinetics of irbesartan are not altered in special populations. J Cardiovasc Pharmacol 40: 112-122.

Martignoni M, Groothuis GM, de Kanter R (2006) Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2: 875-894.

McConnaughey MM, McConnaughey JS, Ingenito AJ (1999) Practical considerations of the pharmacology of angiotensin receptor blockers. J Clin Pharmacol 39: 547-559.

Pierini A, Bocci G, Giorgi M, Owen H, Marchetti V (2012) From humans to dogs and back: the translational lesson of metronomic chemotherapy. Am J Anim Vet Sci 7: 198-212.

Plumb CD (2008) Irbesartan. In: Plumb CD (ed) Plumb’s Veterinary Drug Handbook. Wiley Blackwell, Iowa USA, pp 492-493.

Ruilope L (1997) Human pharmacokinetic/pharmacodynamic profile of irbesartan: a new potent angiotensin II receptor antagonist. J Hypertens 15: S15-20.

Shakya AK, Al-Hiari YM, Alhamami OM (2007) Liquid chromatographic determination of irbesartan in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 848: 245-250.

Simon TA, Gelarden RT, Freitag SA, Kassler-Taub KB, Davies R (1998) Safety of irbesartan in the treatment of mild to moderate systemic hypertension. Am J Cardiol 82: 179-182.

Sweet CS, Rucinska EJ (1994) Losartan in heart failure: preclinical experiences and initial clinical outcomes. Eur Heart J 15: S139-144.

Wernick MB, Ho¨pfner RM, Francey T, Howard J (2012) Comparison of arterial blood pressure measurements and hypertension scores obtained by use of three indirect measurement devices in hospitalized dogs. J Am Vet Med Assoc 240: 962-968.

Polish Journal of Veterinary Sciences

The Journal of Committee of Veterinary Sciences of Polish Academy of Sciences and University of Warmia and Mazury in Olsztyn

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