Back to the Top
Some pharmacokinetic studies use the terms intercompartmental or
distributional clearance. For instance, for a two-compartmental model these
parameters can be calculated from Cld = V1.k12 = V2.k21 (1 = central
compartment en 2 = peripheral compartment).
Could someone explain how these parameters should be interpreted?
In an experiment in which we compared the pharmacokinetics of a drug between
healthy and hypovolemic animals, the following results were obtained
(concentration-time profiles were fitted to a 3-compartmental model);
k10 significantly increased in hypovolemic animals
k12 significantly increased in hypovolemic animals
k21 significantly increased in hypovolemic animals
k13 en k31 were similar in both groups
V1 significantly decreased in hypovolemic animals
V2 was similar in both groups
V3 significantly decreased in hypovolemic animals
Cl1 significantly decreased in hypovolemic animals
Cl2 significantly increased in hypovolemic animals
Cl3 significantly decreased in hypovolemic animals
k10 = elimination rate constant; k12, k21, k13, k31 = first-order rate
constants for drug transfer between compartments; keo = equilibration rate
constant; V1 = central compartment volume; V2 = 2nd peripheral compartment
volume; V3 = 3rd peripheral compartment volume; Cl1 = central compartment
clearance; Cl2 = intercompartmental clearance (rapid distributional
clearance); Cl3 = intercompartmental clearance (slow distributional
clearance)
Could someone please comment on these results.
Many thanks,
Peter De Paepe, MD
Heymans Institute of Pharmacology
De Pintelaan 185
B-9000 Gent
Belgium
TEL : +32 (0)9 240 33 56
FAX : +32 (0)9 240 49 88
e-mail : peter.depaepe.at.rug.ac.be
Back to the Top
Develop a PBPK model - then you won't have to worry about the meaning of
non-physiological parameters.
- Rory Conolly
Back to the Top
[Two more replies - db]
Sender: PharmPK.at.boomer.org
Reply-To: ml11439.aaa.goodnet.com (Michael J. Leibold)
Mime-Version: 1.0
From: ml11439.aaa.goodnet.com (Michael J. Leibold)
Date: Tue, 29 Aug 2000 01:24:12 -0700 (MST)
To: david.-a-.boomer.org
Subject: Re: PharmPK Intercompartmental clearance
The following message was posted to: PharmPK
Dr.Paepe,
In linear compartmental pharmacokinetics, the three-compartment model
is interpreted as follows:
Xo
\
k12 k13
Cpt2<------->Cpt1<------->Cpt3
k21 \ k31
\->k10
This is a linear mammillary model with elimination from a central
compartment wich usually represents the plasma compartment. The system
is described by linear first order differential equations describing
the change in compartmental amounts of drug with time:
dX1/dt= -(k13+k10+k12)X1 + k21X2 +k31X3
dX2/dt= k12X1 - k21X2
dX3/dt= k13X1 -k31X3
From a mathematical perspective, one would expect the K12 and K21
microconstants to be more hemodynamically dependent, since these represent
the distributional properties of the drug as it is transported to the
tissue, and then diffuses back into the circulation. One might expect
these rates to increase in states in which the patient's hemodyamics
are relatively hyperdynamic, as in the case of hypovolemia as the patient's
heart rate increases to maintain bloood pressure. The intercompartmental
clearance between the central and peripheral compartment would be mainly
dependent on the K12 and K21 microconstants, or hemodynamic distribution
forces, rather than the volume of distribution or clearance. This is since
the volume of distribution of the central and tissue compartments would vary,
but perhaps not more than 10-40% of baselne, while the heart rate may double.
Burn patients would provide an example of patient population in which the
distribution microconstants (k12 and k21) increase in the hyperdynamic
burn phase, where the cardiovascular system attempts to maintain blood
pressure in a hypovolemic state resulting from the exudation of fluid
through the surface of the burns. This hypderdynamic phase of the burn
pathophysiology also results in an increase in renal clearance of the
aminoglycoside antibiotics, as found in one of the original study by
Zaske et al in which 47 burn patients required higher gentamicin doses.
However, the increase in renal clearance was also a function of hypoalbu-
nemia and fluid resuscitation in addition to the increased cardiac output.
Although the k12 and k21 microconstants were not supplied in these studies,
aminoglycoside peak and troughs were accurately predicted even though
the peaks were sampled 0-15 minutes post infusion, indicating a rapid
distribution phase (distribution T1/2 in the shorter range of 5-15 minutes).
The third compartment in the case of aminoglycosides is the deep
tissue binding compartment, representing mainly renal tissue binding.
In the case of aminoglycosides, the rate of renal tissue binding would
predict the likelihood of renal toxicity, but seemed less dependent on
cardiovascular hemodynamics. One might expect a decrease in renal tissue
binding in the hyperdynamic state as the aminoglycoside renal clearance
and K21 are increased, diverting drug away from the tissue binding
compartment.
I hope this was of some help!
Mike Leibold, PharmD, RPh
ML11439.aaa.goodnet.com
References
1) Zaske, D.E. et al., Initial dose requirements of gentamicin in
patients with burns, Journ Burn Care Rehab 1991;12:46-50
2) Zaske, D.E. et al., Amikacin pharmacokinetics: wide interpatient
variation in 98 burn patients, Journal of Clinical Pharmacology
1991;31:158-63
3) Zaske, D.E. et al., Increased dosage requirements of gentamicin in
burn patients, The Journal of Trauma 1976;16:824-828
4) Zaske, D.E. et al., The necessity of increased doses of amikacin
in burn patients, Surgery 1978;8:603-608
5) Zaske, D.E. et al., Increased burn patient survival with individualized
doses of gentamcin, Surgery 1982;91142-149
6) Zaske, D.E., et al., Rapid individulization of dosage regimens in 66
burn patients, Burns 1978;7:215-220
7) Schumacher, G.E., Therapeutic Drug Monitoring, Norwalk:Appleton& Lange;
1995;237-294
8) Sawchuk, R.J and Rector, T.S., Drug kinetics in burn patients, Clinical
Pharmacokinetics 1980;5:548-556
9) Gibaldi, M., Perrier, D., Pharmacokinetics, New York, Marcel Dekker
1975
10) Gibaldi, M., Perrier, D., Pharmacokinetics 2nd ed, New York, Marcel Dekker
1982
11) Evans, W.E., Schentag, J.J., Jusko, W.J., Applied Pharmacokinetics 3rd ed,
Vancouver, Applied Therapeutics 1992
---
Sender: PharmPK.aaa.boomer.org
Reply-To:
MIME-Version: 1.0
From:
Date: Tue, 29 Aug 2000 13:00:08 +0200
To: david.at.boomer.org
Subject: Re: PharmPK Re: Intercompartmental clearance
The following message was posted to: PharmPK
An important issue that merits consideration is that of the basic
hypothesis. A physiological model would describe the impact of tissue
perfusion on the PKT profile, this change in tissue perfusion is
secondary to hypovolaemia and its homeostatic control systems. In
order for a physiological model to work you would need to clearly
define the extent of hyovolaemia which is not a distinct
physiological entity but a clinical description of a physiological
range. Given the nature of the haemodynamic response in hypovolaemia
the question is whether the parameters you describe are an instantaneous
reflection of the homeostatic response or descriptive of the clinical
hyovolaemic status.
Given the transient nature of the physiological status the basic PKT
approach will provide as much, sic or possibly more, clinical answers
as would a detailed academic description of a system that is difficult
to define.
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)