Biomedical Engineering Reference
In-Depth Information
Nevertheless, LOQs for tiotropium being 1,000-fold lower were reported by
Ding et al. [
81
] and Wang et al. [
80
] obtained by isocratic chromatography coupled
either to a SQ mass spectrometer for the SIM mode [
81
] or to a QqQ instrument for
MRM mode detection [
80
] (Table
5
). Even though Ding et al. performed a 17-fold
sample concentration after SPE and injected a 1.5 ml plasma equivalent for analysis
[
81
] and Wang et al. concentrated it by a factor of 2.7 after precipitation and LLE
followed by injection of a 107 ml plasma equivalent [
80
] , LOQs appeared surpris-
ingly low. Presumably, the permanent charge of the QTA tiotropium (Fig.
1
) was
primarily responsible for excellent detector response. Mass spectrometric transi-
tions are listed in Table
9
. However, peak plasma concentrations of tiotropium after
inhalation of a single 18 mg dose were as small as 20 pg/ml [
80
] and 13 pg/ml [
81
]
in human PK studies.
Much higher drug concentrations are established when administering atropine as
antidote for OP poisoning.
Abbara et al. performed simultaneous quantification of different antidotes (diaz-
epam, pralidoxime and atropine) typically co-administered for the therapy of anti-
cholinesterase poisoning (Table
5
) [
44
]. PK data resulting from i.m. drug injection
by means of a bi-compartemental auto-injector were calculated from human plasma
concentrations measured by LC-ESI MS/MS with MRM settings. Administration of
2 mg atropine sulphate yielded plasma peak concentrations of about 4 ng/ml 15 min
after injection.
John et al. analysed concentration-time profiles of total atropine and both the
corresponding hyoscyamine isomers after i.v. administration of atropine sulphate
(25 mg) to an organophosphorus (OP) pesticide-poisoned human patient yielding
maximum concentrations of about 600 ng/ml for total atropine and about 300 ng/ml
for each enantiomer found 30 min after injection (Table
5
) [
49
] . Samples were mea-
sured after enzymatic pretreatment (incubation with atropinesterase) prior to LC-ESI
MS/MS analysis in the MRM mode allowing enantioselective quantification of
R
-
and
S
-hyoscyamine [
49
] . Concentration-time pro fi les documented that elimination
of
S
-hyoscyamine in man appeared to be more rapid than of
R
-hyoscyamine. These
findings were similar to data reported by Siluk et al. using a chiral LC-APCI MS
method [
48
] (Table
5
) and by Aaltonen et al. [
45
] and Kentala et al. [
46
] both using
a combination of radio-receptor assay (RRA) and radioimmunoassay (RIA).
The enantioselective procedure of John et al. was also originally applied to moni-
tor concentration-time profiles of atropine and hyoscyamine variants in a PK study
in healthy swine (Table
5
) [
47
]. Mass spectrometric characteristics with respect to
precursor and product ions of atropine and hyoscyamine are summarized in Table
9
.
Following single i.v. administration of 100 mg/kg, maximum plasma concentrations
were found to be 48 ng/ml for atropine and 24 ng/ml for both enantiomers, the dis-
tomer
R
-hyoscyamine and the eutomer
S
-hyoscyamine. In contrast to data in human,
no stereoselective preference for elimination was found in swine thus substantiating
the assumption that hyoscyamine kinetics in man differ from that in swine.
Similar results were obtained with the same LC-ESI MS/MS method when quan-
tifying atropine and hyoscyamine variants in plasma of OP-poisoned swine under
atropine therapy. Swine were topically exposed to the nerve agent VR (302 m g/kg,
t
0
)
