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
Communication
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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)
COOPERATION - PROJECTS
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
: Kolaborativni centar za nuspojave Svjetske
zdravstvene organizacije City: Uppsala, Švedska
Name of institution
: Ministarstvo zdravstva R Hrvatske City: 10000 - Zagreb, Croatia
Name of institution
: WHO Collaborating Centre for Clinical
Pharmacology and Drug Policy Science University of Groningen, Dpt. of
Pharmacology/Clinical Pharmacology City: Groningen, Nizozemska
Name of institution
: Suradnja s časopisima: Pharmaca, J of Clin
Pharmacol Ther Tox, J of Chemotherapy, Clinical Pharmacokinetics City: 10000 - Zagreb, Croatia Other information about the project.