SVIBOR - Project code: 3-01-008


Strossmayerov trg 4, HR - 10000 ZAGREB
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Project code: 3-01-008

The influence of disease on drug pharmacokinetics

Main researcher: VRHOVAC, BOŽIDAR (53374)

Type of research: applied
Duration from: 01/01/91. to 12/31/95.

Papers on project (total): 29
Institution name: Medicinski fakultet, Zagreb (108)
Department/Institute: Section of clinical pharmacology, Department of medicine, University Hospital Medical School, Rebro
Address: Kišpatićeva 12
City: 10000 - Zagreb, Croatia
Phone: 385 (0)41 213 861
Phone: 385 (0)41 233 233/284,279,275
Fax: 385 (0)41 213 861

Summary: The influence of concomitant drugs, diseases, smoking or eating habits in theophylline pharmacokinetics and serum concentrations is striking. The aim of this studz was to investigate the influence of cardiac and hepatic edema upon theophylline pharmacokinetics after oral (6 mgxkg-1) and IV (4 mgxkg-1) administration in a single dose cross-over trial. Pharmacokinetic data (Cmax, AUC(0-6), V.D., t 1/2, relative systemic bioavailability) were measured twice, in edema and after diminution or disappearance of edema by therapy (mainly furosemide with digoxin and or ACE inhibitors as needed). Ten patients completed the study. After oral theophylline administration Cmax was higher in edema (E)64+/-21.2 umolxL-1 vs without edema (WE) 50.8+/-16.4 umolxL-1 (p<0.05). The same is valid for AUC(0-6): E 308.3+/-156.5 umolxh/L, WE 235.2+/-110.7 umolxh/L (p<0.02). Serum concentrations after oral administration were significantly higher in E. Relative bioavailability of oral theophylline decreased after diminution or disappearance of edema whether of cardiac (97.9+/-17.8%) or hepatic (71.0+/-20.3%) origin. There were no differences in serum concentrations after IV injection of aminophylline with regard to the presence or absence of edema. Edema did not influence t1/2, V.D. and AUC(0-6) when aminophylline was given IV. In conclusion the systemic bioavailability of oral theophylline, being an amphoteric drug is higher in edema. However, serum concentrations of theophylline are in the lower range of therapeutic concentrations. Increased bioavailability is therefore probably not of clinical importance for adverse reactions. In spite of that is seems prudent to check serum theophylline concentration in edematous patients who are on regular oral theophylline treatment. The study in nineteen patients with congestive heart failure investigated the influence of edema on medigoxin pharmacokinetics when administered intravenously. Medigoxin was injected twice, at the start and after the diminution or disappearance of edema achieved by diuretics in all patients and vasodilators in six patients. Edema does not influence medigoxin pharmacokinetics and its serum concentrations. In edema: A 7.2+/-5.6 nmolxL-1, B 0.84+/-0.38 nmolxL-1, 3.3+/-2.1 hr-1, 0.035+/-0.021 hr-1, t1/2 30.5+/-19.2 hr, MRT 44.2+/-27.6 hr, Vd 302+/-195 L, V1 37.9+/-21.4 L, Vss 425+/-364 L, AUC (0-12) 11.1+/-5.6 nmolxhr/L, AUC (0-INF) 29.0+/-12.8 nmolxhr/L, without edema: A 7.4+/-5.9 nmolxL-1, B 0.93+/-0.67 nmolxL-1, 2.4+/-1.3 hr-1, 0.036+/-0.025 hr-1, t1/2 32.0+/-29.0 hr, MRT 31.5+/-23.2 hr, Vd 338+/-178 L, V1 35.8+/-23.5 L, Vss 469+/-351 L, AUC(0-12) 11.2+/-5.3 nmolxhr/L, AUC(0-INF) 25.2+/-11.0 nmolxhr/L. In conclusion, a single intravenous dose of medigoxin need not be modified in patients with edema. The analysis of data obtained in the study of verapamil pharmacokinetics in patients (eight, 6 of cardial, 2 with hepatic origin) with edema is underway. Two patients could not finish the II. part of the study. One due to side effect, the other died due to its disease. The influence of renal disease using the ciprofloxacin model in patients on hemodialysis could not been investigated since the responsible collaborator does not work anymore in the Clinical Hospital Centre. At this moment the investigation of aspirin pharmacokinetic (low antiplatelet dose of 100 mg) and of ACE inhibitor in edema is in its preparatory stage. The condition is the elaboration of analytical methods for measurement of these agents in serum.

Keywords: edema and pharmacokinetics, theophylline, digoxin, verapamil, aspirin, ACE inhibitors, furosemide, drug interactions

Research goals: Aims: -to determine the changes of pharmacokinetics of chosen watersoluble drugs with a small therapeutic ratio in diseases with edema. It was expected that the rate and extent of absorption will be decreased, volume of distribution increased and the rate of metabolism of ionized and hydrophylic drugs decreased as well. Expected results: Data obtained should enable individualization of therapy withdrugs of small therapeutic ratio in edematous conditions.Disappearance or appearance of edema (potentially could considerably influence serum steady state drug concentration, so affecting its therapeutic, or toxic effects. The most important benefit of these investigations could be expected in the field of individualization of drug use. The results could enable the elaboration of models for investigation of the influence of diseases on the pharmacokinetics of certain therapeutic groups. (see summary)


  1. Name of project: Oblikovanje empirijske terapije bolničkih infekcija (prihvaćeno kao ratni projekt - infekcije u ranjenika) 1991-1992 i početak 93.
    Name of institution: Medicinski fakultet
    City: 10000 - Zagreb, Croatia


  1. Name of institution: Farmaceutska industrija (Pliva, Lek, Krka, Alfamed, Belupo)
    City: 10000 - Zagreb, Croatia

  2. Name of institution: Kolaborativni centar za nuspojave Svjetske zdravstvene organizacije
    City: Uppsala, Švedska

  3. Name of institution: Ministarstvo zdravstva R Hrvatske
    City: 10000 - Zagreb, Croatia

  4. Name of institution: WHO Collaborating Centre for Clinical Pharmacology and Drug Policy Science University of Groningen, Dpt. of Pharmacology/Clinical Pharmacology
    City: Groningen, Nizozemska

  5. Name of institution: Suradnja s časopisima: Pharmaca, J of Clin Pharmacol Ther Tox, J of Chemotherapy, Clinical Pharmacokinetics
    City: 10000 - Zagreb, Croatia

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Last update: 10/18/95