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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 5/2006

01-05-2006 | Review Article

The Influence of Cardiovascular Physiology on Dose/Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Relationships

Authors: Dr Pietro Fagiolino, Rosa Eiraldi, Marta Vázquez

Published in: Clinical Pharmacokinetics | Issue 5/2006

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Abstract

Inter- and intraindividual variability in the relationship between dose and clinical — or pharmacodynamic — response of a drug can be analysed in two steps: firstly, by considering the plasma pharmacokinetic response to a given dose and, secondly, by the connection between both pharmacokinetic and pharmacodynamic responses.
As the cardiovascular system is the means of transport of endogenous and exogenous substances, blood flow fraction destined to each organ determines the relative mass of solute in plasma, which is constantly in contact with the tissue. Hence, not only the rate but also the extent of drug transfer would be increased when tissues are irrigated by a higher fraction of cardiac output.
Aging and circadian rhythms present similar cardiac output distribution patterns when moving from young to aged adult and from nocturnal to diurnal hours. These two changes lead to an increased blood flow delivery to the extra-splanchnic-renal region in the elderly and in the morning, but with a decreased cardiac output in aged individuals and an increased one during the day.
This scenario allows us to forecast substance concentrations outside the blood vessels, which are responsible for the extent of drug elimination and the intensity of drug effect. So available data on disposition and pharmacodynamics of drugs might be explained from another point of view that challenges current knowledge. Furthermore, the administration of cardiovascular active drugs might reverse the chronological sequence between pharmacokinetic and pharmacodynamic responses, since they could modify blood flow distribution.
Literature
1.
Levy G. Predicting effective drug concentrations for individual patients: determinants of pharmacodynamics variability. Clin Pharmacokinet 1998; 34: 323–33PubMedCrossRef
2.
Hämmerlein A, Derendorff H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly: clinical implications. Clin Pharmacokinet 1998; 35: 49–64PubMedCrossRef
3.
Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (part I). Clin Pharmacokinet 1991; 21: 165–77PubMedCrossRef
4.
Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (part II). Clin Pharmacokinet 1991; 21: 262–73PubMedCrossRef
5.
Turnheim K. Drag dosage in the elderly: is it rational? Drags Aging 1998; 13: 357–79CrossRef
6.
Turnheim K. When drag therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003; 38: 843–53PubMedCrossRef
7.
Ritschel WA. Chronopharmacokinetics. Pharm Internat 1984; 5: 116–22
8.
Lemmer B. Chronopharmacological aspects of PK/PD modeling. Int J Clin Pharmacol Ther 1997; 35: 458–64PubMed
9.
Redfem P, Lemmer B, editors. Handbook of experimental pharmacology: physiology and pharmacology of biological rhythms. Vol. 125. Berlin: Springer-Verlag, 1997
10.
Eichler HG, Müller M. Drug distribution: the forgotten relative in clinical pharmacokinetics. Clin Pharmacokinet 1998; 34: 95–9PubMedCrossRef
11.
12.
Cheitlin MD. Cardiovascular physiology: changes with aging. Am J Geriate Cardiol 2003; 12: 9–13CrossRef
13.
McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56: 163–84PubMedCrossRef
14.
McElnay JC, D’Arcy PF. Age and genetic factors in drug interactions. In: D’Arcy PF, McElnay JC, Welling PG, editors. Handbook of experimental pharmacology: mechanisms of drug interactions. Vol. 122. Berlin: Springer-Verlag, 1996: 279–304CrossRef
15.
Le Couteur DG, McLean AJ. The aging liver: drag clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet 1998; 34: 359–73PubMedCrossRef
16.
Steimer JL, Ebelin ME, Van Bree J. Pharmacokinetic and pharmacodynamics data and models in clinical trials. Eur J Drug Metab Pharmacokinet 1993; 18: 61–76PubMedCrossRef
17.
Meibohm B, Derendorf H. Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling. Int J Clin Pharmacol Ther 1997; 35: 401–13PubMed
18.
Gourlay SG, Benowitz NL. Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray, and intravenous nicotine. Clin Pharmacol Ther 1997; 62: 453–63PubMedCrossRef
19.
Fagiolino P. The influence of cardiac output distribution on the tissue/plasma drug concentration ratio. Eur J Drag Metab Pharmacokinet 2002; 27: 79–81CrossRef
20.
Fagiolino P, Wilson F, Samaniego E, et al. In vitro approach to study the influence of the cardiac output distribution on drug concentration. Eur J Drag Metab Pharmacokinet 2003; 28: 147–53CrossRef
21.
Fagiolino P. Multiplicative dependence of the first order rate constant and its impact on clinical pharmacokinetics and bioequivalence. Eur J Drag Metab Pharmacokinet 2004; 29: 43–9CrossRef
22.
Olano I, Vázquez M, Fagiolino P. Chronopharmacokinetics of carbamazepine and its metabolite 10, 11-epoxide. J Pharm Clin 1998; 17: 153–6
23.
Fagiolino P. Monitorización de fármacos en saliva: aplicaciones biofarmacéuticas, farmacocinéticas y terapéuticas. Montevideo: Comisión Sectorial de Investigación Cientifica (CSIC) — Universidad de 1a República O. del Uruguay, 1999
24.
Fagiolino P, Duré MC, Vázquez M. Sympathetic tone evaluation in patients treated with phenytoin and carbamazepine [in Spanish]. Acta Farm Bonaerense 2000; 19: 119–24
25.
Schmucker DL. Liver function and phase I drag metabolism in the elderly: a paradox. Drags Aging 2001; 18: 837–51CrossRef
26.
Kaminsky LS, Zhang QY. The small intestine as a xenobiotic-metabolizing organ. Drug Metab Dispos 2003; 31: 1520–5PubMedCrossRef
27.
Gibbs MA, Hosea NA. Factors affecting the clinical development of cytochrome P450 3A substrates. Clin Pharmacokinet 2003; 42: 969–84PubMedCrossRef
28.
Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 2005; 44: 33–60PubMedCrossRef
29.
Lin JH, Chiba M, Baillie TA. Is the role of the small intestine in first-pass metabolism overemphasized? Pharmacol Rev 1999; 51: 135–58PubMed
30.
von Richter O, Burk O, Fromm MF, et al. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 2004; 75: 172–83CrossRef
31.
Kivisto KT, Niemi M, Fromm MF. Functional interaction of intestinal CYP3A4 and P-glycoprotein. Fundamental Clin Pharmacol 2004; 18: 621–6CrossRef
32.
Hanratty CG, McGlinchey P, Johnston GD, et al. Differential pharmacokinetics of digoxin in elderly patients. Drugs Aging 2000; 17: 353–62PubMedCrossRef
33.
Labaune JP. Pharmacocinétique: principes fondamentaux. Paris: Masson SA, 1984
34.
Koren G. Clinical pharmacokinetic significance of the renal tubular secretion of digoxin. Clin Pharmacokinet 1987; 13: 334–47PubMedCrossRef
35.
Timmis GC, Westveer DC, Nelson TA, et al., editors. Congestive heart failure and pulmonary edema, digitalis. In: Cardiovascular Review 1984. Orlando (FL): Academic Press, 1984: 521
36.
Newton R, Broughton LJ, Lind MJ, et al. Plasma and salivary pharmacokinetics of caffeine in man. Eur J Clin Pharmacol 1981; 21: 45–52PubMedCrossRef
37.
Tang-Liu DDS, Williams RL, Riegelman S. Nonlinear theophylline elimination. Clin Pharmacol Ther 1982; 31: 358–69PubMedCrossRef
38.
Giessmann T, May K, Modes C, et al. Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans. Clin Pharmacol Ther 2004; 76: 192–200PubMedCrossRef
39.
Bélanger PM, Braguerolle B, Labrecque G. Rhythms in pharmacokinetics: absorption, distribution, metabolism and excretion. In: Redfem P, Lemmer B, editors. Handbook of experimental pharmacology, vol. 125: physiology and pharmacology of biological rhythms. Berlin: Springer-Verlag, 1997: 177–204
40.
Lemmer B, Sheidel B, Behne S. Chronopharmacokinetics and chronopharmacodynamics of cardiovascular active drugs: propranolol, organic nitrates, nifedipine. Ann N Y Acad Sci 1991; 618: 166–81PubMedCrossRef
41.
Lemmer B, Scheidel B, Blume H, et al. Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects. Eur J Clin Pharmacol 1991; 40: 71–5PubMedCrossRef
42.
Zerbe H, Luckow V, Cawello W, et al. Isosorbide-5-nitrate sustained-release pellets: an example of computer-supported drug development. Pharm Res 1985; 3: 30–6CrossRef
43.
St-Pierre MV, Spino M, Isles AF, et al. Temporal variation in the disposition of theophylline and its metabolites. Clin Pharmacol Ther 1985; 38: 89–95PubMedCrossRef
44.
Bosch J, García-Pagán JC. Enfermedades vasculares del hígado. In: Farreras P, Rozman C, edtiors. Medicina Interna, Vol. I, 14a edición. Madrid: Harcourt SA, 2000: 435–43
45.
Decousus H, Ollagnier M, Cherrah Y, et al. Chronokinetics of ketoprofen infused intravenously at a constant rate. Ann Rev Chronopharmacol 1986; 3: 321–4
46.
Feria M. Fármacos analgésicos, antitérmicos y antiinflamatorios no esteroideos. In: Flórez J, Armijo JA, Mediavilla A, editors. Farmacologia humana. 4a edición. Barcelona: Masson SA, 2003: 375–408
47.
Guyton AC, Hall JE. Texbook of medical physiology. 9th ed. [in Spanish]. Mexico: McGraw-Hill Interamericana Editors, 1997: 343–60
48.
Dickson CJ, Schwartzman MS, Bertino JS. Factors affecting aminoglycoside disposition: effects of circadian rhythm and dietary protein intake on gentamicin pharmacokinetics. Clin Pharmacol Ther 1986; 39: 325–8PubMedCrossRef
49.
van Acker BA, Koomen GC, Koopman MG, et al. Discrepancy between circadian rhythms of inulin and creatinine clearance. J Lab Clin Med 1992; 120: 400–10PubMed
50.
Koopman MG, Koomen GC, Krediet RT, et al. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci 1989; 77: 105–11PubMed
51.
Bleyzac N, Allard-Latour B, Laffont A, et al. Diurnal changes in the pharmacokinetic behavior of amikacin. Ther Drug Monit 2000; 22: 307–12PubMedCrossRef
52.
Voogel AJ, Koopman MG, Augustinus AM, et al. Circadian rhythms in systemic hemodynamics and renal function in healthy subjects and patients with nephritic syndrome. Kidney Int 2001; 59: 1873–80PubMedCrossRef
53.
54.
Wedlund PJ, Levy RH. Time-dependent kinetics VII: effect of diurnal oscillations on the time course of carbamazepine autoinduction in the rhesus monkey. J Pharm Sci 1983; 72: 905–9PubMedCrossRef
55.
Miura T, Kojima R, Sugiura Y, et al. Effect of aging on the incidence of digoxin toxicity. Ann Pharmacother 2000; 34: 427–32PubMedCrossRef
56.
Sowinski K, Forrest A, Wilton J, et al. Effect of aging on atenolol pharmacokinetics and pharmacodynamics. J Clin Pharmacol 1995; 35: 807–14PubMed
57.
van Baak MA. Influence of exercise on the pharmacokinetics of drugs. Clin Pharmacokinet 1990; 19: 32–43PubMedCrossRef
58.
Jogestrand T, Sundqvist K. Effect of physical exercise on the digoxin concentrations in skeletal muscle and serum in man. Clin Physiol 1981; 1: 99–104CrossRef
59.
Joreteg T, Jogestrand T. Physical exercise and digoxin binding to skeletal muscle: relation to exercise intensity. Eur J Clin Pharmacol 1983; 25: 585–8PubMedCrossRef
60.
Joreteg T, Jogestrand T. Physical exercise and binding of digoxin to skeletal muscle: effect of activation frequency. Eur J Clin Pharmacol 1984; 27: 567–70PubMedCrossRef
61.
Jorgestrand T, Andersson K. Effect of physical exercise on the pharmacokinetics of digoxin during maintenance treatment. J Cardiovasc Pharmacol 1989; 14: 73–6CrossRef
62.
Schmidt TA, Bundgaard H, Olesen HL, et al. Digoxin affects potassium homeostasis during exercise in patients with heart failure. Cardiovasc Res 1995; 29: 506–11PubMed
63.
Serafin WE. Fármacos utilizados para el tratamiento del asma. In: Goodman & Gilman’s the pharmacological basis of therapeutics. 9th ed. [in Spanish]. México: McGraw-Hill Interamericana Editores SA, 1996: 707–31
64.
Tang-Liu DDS, Tozer TN, Riegelman S. Urine flow-dependence of theophylline renal clearance in man. J Pharmacokinet Biopharm 1982; 10: 351–64PubMed
65.
Trnavska Z, Rejholec V, Elis J, et al. Comparative pharmacokinetic analysis of theophylline in serum and saliva. Int J Clin Pharm Res 1987; 7: 329–35
66.
Shah VP, Riegelman S. GLC determination of theophylline in biological fluids. J Pharm Sci 1974; 63: 1283–5PubMedCrossRef
67.
Ishizaki T, Kubo M. Incidence of apparent Michaelis-Menten kinetic behavior of theophylline and its parameter (Vmax and Km) among asthmatic children and adults. Ther Drug Monit 1987; 9: 11–20PubMedCrossRef
68.
Tang-Liu DDS, Williams RL, Riegelman S. Nonlinear theophylline elimination. Clin Pharmacol Ther 1982; 31: 358–69PubMedCrossRef
69.
Payssé H, Fagiolino P, Vázquez M, et al. Preliminary study of the theophylline chronopharmacokinetics by salivary assay [in French]. J Pharm Clin 1997; 16: 60–4
70.
Orosa E, Payssé H, Mérola J, et al. Incidence of the kinetics of nonlinear elimination in the posology with theophylline [in Spanish]. Rev OFIL 1993; 3: 18–21
71.
Le Couteur DG, Fraser R, Hilmer S, et al. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet 2005; 44: 187–200PubMedCrossRef
Metadata
Title
The Influence of Cardiovascular Physiology on Dose/Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Relationships
Authors
Dr Pietro Fagiolino
Rosa Eiraldi
Marta Vázquez
Publication date
01-05-2006
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 5/2006
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/00003088-200645050-00001

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