Biomedical Engineering Reference
In-Depth Information
1.6
Toxicological Considerations
The volume of distribution (
V
D
) quantifies the distribution of a drug between plasma
and the rest of the body after oral or parental application. Drugs which only distrib-
ute in blood show a
V
D
of ~0.05 L/kg, whereas drugs distributed in extracellular
water have a
V
D
of ~0.2 L/kg; the total body water volume is 0.55 L/kg. APs are
lipid soluble weak bases which are easily taken up into body fat and organs, there-
fore generally show a large
V
D
. Plasma protein binding, also referred to as the “frac-
tion bound” (Fb), is the percentage of a drug bound to plasma proteins after its
admission. Only the unbound fraction of a drug will cause a pharmacological effect
and can be detected using analytical methods. Despite their high
V
D
, most common
APs show a high Fb. Both parameters significantly contribute to low or undetectable
blood concentrations.
Therapeutic blood concentrations described in this chapter are based on studies
that relate to drug concentrations measured at steady state of patients treated with
recommended daily doses of a drug. However, the same dose of a drug can result in
considerably different plasma concentrations in different individuals, depending on
factors such as diet, lifestyle, comedication, and genetic makeup resulting in altered
absorption, distribution, and elimination of drugs.
The terminal elimination half-life (
t
1/2
) of a drug is not dose-dependent and can
range from a few days up to several weeks for APs (
t
1/2
of up to 16 weeks with a very
large variation has been described for Flupentixol-decanoate [
25
] ). Importantly, the
time required to reach steady state depends only on
t
1/2
of a compound. Steady state
is usually reached after five
t
1/2
. It is usually not advisable to measure plasma con-
centrations before this equilibrium is reached except for drugs with very long
t
1/2
such as depot-formulations. This is done in order to ensure that patients with
impaired metabolism or excretion are not at risk of reaching above-therapeutic drug
concentrations at their initial dosage regimen.
Table
1
shows the
V
D
,
t
1/2
, Fb, and therapeutic blood concentrations of common APs.
2
Detection of APs Using LC-MS Techniques
2.1
Instrumentation
Until approximately a decade ago, gas chromatography mass spectrometry (GC-
MS) was considered the
gold standard
of analysis and quantification of drugs
and their metabolites in biological matrices [
26
]. In order to be suitable for
GC-analysis, a compound needs to be volatile and thermally stable to such an
extent that it can be transferred into a gas phase. Unfortunately, several APs,
such as risperidone are unstable and are not amenable to direct GC analysis due
to their chemical properties. In addition, standard GC-MS instruments do often
not provide sufficient sensitivity to detect the low concentrations in which certain
