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EC number: 232-077-3
CAS number: 7785-26-4
None of the volunteers reported any adverse health effects due to the
supplementation with 10 mg of αPN. Though, all volunteers mentioned a
characteristic aromatic smell of the exhaled breath which occurred about
1 h after oral exposure and subsequently vanished within 2–3 h after
exposure. It was assume that respiratory elimination of unmetabolized
αPN was a substantial elimination pathway, as well, which may have
contributed to a large extend to the 78 % of the oral dose which was not
recovered in form of renal metabolites. This is in accordance with the
volunteers’ reports on olfactory perception during the exposure
experiments. However, the amount of αPN exhaled was not quantified.
The synchronous and steep metabolite time courses observed in blood and
urine may be explained by simultaneous and competing reactions during
first-pass metabolism. This first-pass effect, which rapidly yields in
polar phase I and II metabolites, is presumably responsible for the low
blood concentrations as well as the short elimination half-lives in the
first elimination phases. The second, slower elimination phases observed
for all metabolites are most probably caused by release of low amounts
of αPN or its metabolites from tissue compartments. However, the
cumulative elimination indicate that the second phase only plays a minor
role to the cumulatively eliminated amount. At the elimination peak, MYR
and MYRA are almost entirely conjugated to glucuronic acid (or
sulphate), whereas cVER and tVER are only conjugated up to 76 %. This
effect may be due to steric hindrance of the secondary hydroxyl groups
caused by the bicyclic backbone or due to instability of the conjugates.
of the blood kinetics ofαPN metabolites
after oral exposure to 9.0±0.4
(mean val- ues±range;n=2
not completed within 5 h observation period
of the renal αPN
metabolite elimination kinetics after oral exposure to 9.0±0.4
Share of oral dose(%)
to reach maximum renal excretion;t1/2elimination
under the renal excretion vs. time curve (from time 0 to final sampling
excreted urine volume
In a metabolism study, four healthy human volunteers were orally
exposed to a single dose of 9 mg of (1S,5S)-(−)-α- pinene (αPN) via
spiked gelatin capsules. Each volunteer gave one urine sample before
administration and subsequently collected each urine sample within 24 h
after administration. Blood samples were collected directly after
administration of the capsule and every hour until 5 hours exposure for
2 volunteers. The concentration of the αPN metabolites were determined
using a very specific and sensitive GC-PCI-MS/MS procedure.
Concentration of αPN was analysed in blood by HS-GC-MS procedure.
αPN metabolites cVER (cis- verbenol) , tVER (trans-verbenol) , and
MYR (myrtenol) were detected in blood samples over the entire blood
sampling period of 1–5 h, unmetabolised αPN were below the limit of
The metabolite concentrations showed synchronous time courses even
though the levels were low and varied between the two volunteers.
Metabolite blood levels were low. The non-detection of αPN in blood
after low oral doses in contrast to the detectable metabolite levels
indicates a fast and approximately entire pre-systemic metabolism such
as hepatic or intestinal firstpass metabolism.
αPN metabolites were detected in urine in considerably higher
amounts in contrast to blood levels. The low blood concentrations
compared to the high urinary levels, thus, indicate a fast transfer from
blood to urine and a rapid renal elimination.
In addition to the known and established αPN metabolites cVER and
tVER, the relevance of MYR and MYRA as products of the human in vivo
metabolism of αPN was confirmed. Two unknown human metabolites were
identified and these structures could be predicted as 4-hydroxymyrtenic
acid (MYRA-4-OH) and dihydromyrtenic acid (DHMYRA).
Human in vivo metabolism of αPN is similarly dominated by
extensive oxidation reactions on the methyl side-chains yielding in
carboxylic acid structures. Nonetheless, only 22% of the applied dose
was quantified as metabolite. Thus, further metabolites and the share of
αPN eliminated unchanged via lungs remain unclear.
Human metabolism of αPN proceeds fast and the body is almost
entirely cleared from the metabolites 10 h after exposure
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