Percutaneous absorption of the montoterperne carvone: implication of stereoselective metabolism on blood levels.

Article abstract of DOI:10.1211/0022357011775965

The purpose of this study was to determine whether an enantioselective difference in the metabolism of topically applied R-(-)- and S-(+)-carvone could be observed in man. In a previous investigation we found that R-(-)- and S-(+)-carvone are stereoselectively biotransformed by human liver microsomes to 4R,6S-(-)- and 45,6S-(+)-carveol, respectively, and 4R,6S-(-)-carveol is further glucuronidated. We therefore investigated the metabolism and pharmacokinetics of R-(-)- and S-(+)-carvone in four healthy subjects using chiral gas chromatography as the analytical method. Following separate topical applications at a dose of 300 mg, R-(-)- and S-(+)-carvone were rapidly absorbed, resulting in significantly higher Cmax levels for S-(+)-carvone (88.0 vs 23.9 ng mL(-1)) and longer distribution half-lives (t(1/2alpha)) (19.4 vs 7.8 min), resulting in 3.4-fold higher areas under the blood concentration-time curves (5420 vs 1611 ng min mL(-1)). The biotransformation products for both enantiomers in plasma were below detection limit. Analysis of control- and beta-glucuronidase pretreated urine samples, however, revealed a stereoselective metabolism of R-(-)-carvone to 4R,6S-(-)-carveol and 4R,6S-(-)-carveol glucuronide. No metabolites could be found in urine samples after S-(+)-carvone application. These data indicate that stereoselectivity in phase-I and phase-II metabolism has significant effects on R-(-)- and S-(+)-carvone pharmacokinetics. This might serve to explain the increased blood levels of S-(+)-carvone.

Full text of DOI:10.1211/0022357011775965

Journal of
Pharmacy and Pharmacology
JPP 2001, 53: 637–642
# 2001 The Authors
Received October 5, 2000
Accepted January 30, 2001
ISSN 0022-3573
Percutaneous absorption of the montoterpene carvone:
implication of stereoselective metabolism on blood
levels
Walter Jager, Marion Mayer, Gottfried Reznicek, and Gerhard Buchbauer
Abstract
The purpose of this study was to determine whether an enantioselective difference in the
metabolism of topically applied R-(k)- and S-(j)-carvone could be observed in man. In a
previous investigation we found that R-(k)- and S-(j)-carvone are stereoselectively biotrans-
formed by human liver microsomes to 4R,6S-(k)- and 4S,6S-(j)-carveol, respectively, and
4R,6S-(k)-carveol is further glucuronidated. We therefore investigated the metabolism and
pharmacokinetics of R-(k)- and S-(j)-carvone in four healthy subjects using chiral gas
chromatography as the analytical method. Following separate topical applications at a dose of
300 mg, R-(k)- and S-(j)-carvone were rapidly absorbed, resulting in significantly higher Cmax
1
levels for S-(j)-carvone (88.0 vs 23.9 ng mL 1) and longer distribution half-lives (t2α) (19.4 vs
−
7.8 min), resulting in 3.4-fold higher areas under the blood concentration–time curves (5420 vs
1611 ng min mL 1). The biotransformation products for both enantiomers in plasma were
−
below detection limit. Analysis of control- and β-glucuronidase pretreated urine samples,
however, revealed a stereoselective metabolism of R-(k)-carvone to 4R,6S-(k)-carveol and
4R,6S-(k)-carveol glucuronide. No metabolites could be found in urine samples after S-(j)-
carvone application. These data indicate that stereoselectivity in phase-I and phase-II
metabolism has significant effects on R-(k)- and S-(j)-carvone pharmacokinetics. This might
serve to explain the increased blood levels of S-(j)-carvone.
Institute of Pharmaceutical
Chemistry, University of Vienna,
Althanstrasse 14, A-1090 Vienna,
Austria
Walter Jager, Marion Mayer,
Gerhard Buchbauer
Institute of Pharmacognosy,
University of Vienna, Austria
Introduction
Gottfried Reznicek
The R-(k)- and S-(j)-enantiomers of the monoterpene ketone carvone are found
in various plants. While S-(j)-carvone is the main constituent of the essential oil
of caraway (Carum carvi), the oil of spearmint leaves (Mentha spicata var. crispa)
contains about 50% of R-(k)-carvone besides other terpenes. Both enantiomers
are not only different in odour and taste, but they also have different use in the food,
fragrance and pharmaceutical industries (Ziegler 1982; Wichtl 1997). Because of its
minty odour and taste, large amounts of R-(k)-carvone are frequently added to
toothpastes, mouth washes and chewing gums. S-(j)-Carvone possesses the
typical caraway aroma and is therefore mainly used as a taste enhancer in the food
and fragrance industries. Due to its spasmolytic effect, S-(j)-carvone is also used
as a stomachic and carminative in many pharmaceutical formulations (Wichtl
1997). Furthermore, in combination with other essential oils, S-(j)- and R-(k)-
carvone are applied in aromatherapy massage treatments for nervous tension and
several skin disorders. Though the acute toxicity of both enantiomers is low, with
Correspondence: W. Jager,
Institute of Pharmaceutical
Chemistry, University of Vienna,
Althanstrasse 14, A-1090 Vienna,
Austria. E-mail:
walter.jaeger!univie.ac.at
Funding and acknowledgement:
This study was supported by the
grant P 11606-Med from the
Austrian Science Foundation,
Vienna, Austria. We also
acknowledge Dragoco Comp.,
Vienna, Austria, for their
interest in this study. Dedicated
to Prof. Dr Peter Heistracher for
his 70th birthday.
1
1
−
reported LD50 (median lethal dose) values of 1640 mg kg in rats and 766 mg kg
−
637

638
Walter Jager et al
in guinea-pigs (Opdyke 1973, 1978), the high concen- stirring for 12 h the final product was extracted with
trations in many products for massage treatments and diethylether and the organic layer was evaporated under
the large amounts consumed as food additives and reduced pressure. The presence of sucrose dramatically
in dental formulations justifies the determination of enhanced axial entrance of the hydride since more than
their blood levels after absorption.
75% of (4R,6S)-(k)- and (4S,6S)-(j)-carveol but less
We recently demonstrated that R-(k)-carvone rapi- than 25% of the (4R,6R)-(k) and -(4S,6R)-(j) stereo-
dly penetrates human skin, resulting in measureable isomers were formed as determined by chiral GC. The
blood levels (Fuchs et al 1997). Using rat and human residue was dissolved in dichloromethane and further
liver microsomes we could also show a stereoselective purified by preparative GC as described previously
biotransformation when each entantiomer was incu- (Jager et al 2000).
batedseparatelywith liver microsomes(Jageretal2000).
Topical application
4R,6S-(k)-Carveol was NADPH-dependently formed
from R-(k)-carvone, whereas 4S,6S-(j)-carveol was
produced from S-(j)-carvone. In the presence of
uridine 5h-diphosphoglucuronic acid (UDPGA), 4R,
6S-(k)-carveol and not 4S,6S-(j)-carveol was further
conjugated with glucuronic acid. Glucuronidation of
the formed hydroxyl group is in accordance with litera-
ture as it has been found for menthol and other
hydroxylated terpenes (Yamaguchi et al 1994; Green
et al 1995; Green & Tephly 1996).
A target amount of 1.5 g of peanut oil containing 300 mg
of R-(k) and S-(j)-carvone, respectively, were spread
on a defined skin area of the lower abdomen (approx-
imately 376 cm2) of four healthy subjects (body weight
54p5.5 kg, age20p3.0years, 1nonsmoker, 3 smokers).
The subjects provided written informed consent and the
protocol was approved by the local ethics committee.
To avoid possible uptake of the fragrance compound by
inhalation the subjects wore a breathing mask (size 6,
King Systems Corp., Noblesville, IN). Blood samples
(8 mL) were drawn from the left cubital vein at 0, 5, 10,
15, 20, 25, 30, 40, 55, 70, 85 and 100 min after application
of R-(k)- and S-(j)-carvone-containing peanut oil,
respectively, and collected in chilled evacuated tubes
(Vacutainer 10 mL, Becton Dickinson, Heidelberg,
Germany). Plasma was obtained by centrifugation of
blood for 10 min at approximately 2000 g at 4mC. Urine
samples were collected in teflon-capped bottles and
pooled during the following time intervals: 0–4, 4–8,
8–12 and 12–24 h after dosing. During the collection
interval, the urine was stored at approximately 4mC.
At the end of each collection period, the volume of
urine was recorded, and the samples were frozen
immediately on dry ice and stored at k20mC until
analysis (volumes of urine for R-(k)- and S-(j)-
carvone: 185p60 mL and 162p25 mL at 0–4 h;
179p30 mL and 192p64 mL at 4–8 h; 177p30 mL
and 184p57 mL at 8–12 h; 245p30 mL and
177p59 mL at 12–24 h, respectively). Starting a
week before the massage, all food and cosmetics
containing R-(k) and S-(j)-carvone were avoided.
The aim of this study was to investigate the im-
plication of stereochemistry on the metabolism and
pharmacokinetics of R-(k)- and S-(j)-carvone in
healthy subjects after topical absorption from peanut
oil using a sensitive chiral gas chromatography (GC)
method to analyse blood and urine samples.
Materials and Methods
Materials
R-(k)- and S-(j)-carvone (p-mentha-6,8-dien-2-one;
optical purity 99%), (k)-carveol (p-mentha-6,8-dien-
2-ol; optical purity 97%; (Z\E: 50:50)), 2,2-dimethoxy-
propane and dimethyl sulfoxide (DMSO) were obtained
from Aldrich, Munich, Germany; β-glucuronidase type
B-3 from bovine liver was purchased from Sigma,
Munich, Germany; rac-piperitone (1-methyl-4-iso-
propyl-1-cylohexen-3-one; (R\S: 85\15)) was obtained
from Roth, Karlsruhe, Germany and methanol (Lichro-
solv) was from Merck, Darmstadt, Germany. All other
chemicals and solvents were of analytical grade and
used without further purification.
Sample extraction
Synthesis of carveol isomers
After adding piperitone as the internal standard (5 µL
1
−
Stereoselective reductions of R-(k)- and S-(j)-carvone of a stock solution of 10 µg mL ) to 2 mL of plasma
(1.6 mmol) were carried out at room temperature with and 2.5 mL of urine, samples were passed through C18
NaBH4 (3.2 mmol) in aqueous solution of sucrose columns (International Technology Ltd, Mid Glam-
(1 m) according to the literature (Herve du Penhoat et organ, UK), equilibrated with 3 mL of methanol and
al 1991; Adams & Lerner 1992; Denis et al 1996). After water, respectively. Thecolumns werewashedwith 2 mL

639
Absorption and stereoselective metabolism of carvone
125
100
250000
A
R-(–)-Carvone
S-(+)-Carvone
200000
150000
100000
50000
0
75
50
25
0
0
10
20
30
40
50
Retention time (min)
0
10 20 30 40 50 60 70 80 90 100
Time (min)
250000
200000
150000
100000
50000
0
B
Figure 1 Plasma concentrations of R-(k)- and S-(j)-carvone in
healthy subjects, administered as a single topical application of
300 mg. Data are meanps.d., n l 4.
Table 1 Mean pharmacokinetic parameters of R-(k)-carvone and
S-(j)-carvone after dermal administration at a single dose of 300 mg
to healthy subjects.
Parameter
R-(V)-Carvone S-(T)-Carvone Stereoselective
indexa
0
10
20
30
40
50
1
−
Cmax (ng mL
)
23.9p2.3
27.8p3.1
2.3p0.53
7.8p2.3
33.5p6.1
1611p28.0
88.0p2.6
32.4p2.3
2.2p0.15
19.4p0.72
37.5p12.4
5420p145
0.27**
0.86
Retention time (min)
Tmax (min)
1
−
ka (h
)
1.07
Figure 2 Representative chiral GC chromatogram of a β-glucuro-
nidase pretreated plasma sample after the topical application of R-
(k)-carvone (A) or S-(j)-carvone (B) to a healthy male subject. (k)-
C, R-(k)carvone; (j)-C, S-(j)-carvone; R-IST, R-(k)-piperitone;
S-IST, S-(j)-piperitone.
t12α (min)
t12β (min)
0.40**
0.89
AUC (ng min
1
0.30**
−
mL
)
Each value represents the meanps.d. of four percutaneous admin-
istrations. aRatio of parameters between both enantiomers; **P !
samples were spiked with R-(k)- and S-(j)-carvone,
0.01 compared with control. Cmax, peak plasma concentration; Tmax
,
1
time to reach the peak plasma concentration; ka, absorption rate
constant; t12α, and t21β, distribution and elimination half-lives, re-
spectively; AUC, area under the blood concentration–time curve
from 0 to 100 min.
−
respectively, to give final concentrations of 10 ng mL
(n l 5). Theextentof racemisationforboth enantiomers
after 24 h at 4mC and k20mC was below detection limit.
Chiral GC analysis
of water and R-(k)- and S-(j)-carvone and their For chiral separation of carvone and its metabolites, a
metabolites were eluted with 0.3 mL of methanol Carlo-Erba HRGC 5160 Mega Series instrument with a
(recovery " 95%) and immediately analysed by chiral flame ionization detector and a 40 mmi0.25 mm
GC analysis. For detection of glucuronides, selected Chiraldex β-cyclodextrin trifluoroacetyl column con-
plasma (2 mL) and urine samples (2.5 mL) were incu- nected with a 5 mmi0.25 mm retention gap guard
bated with 50 µL of β-glucuronidase (50000 U) in the column (both Astec, Whippany, NJ) were used. The
1
−
presence of piperitone (5 µL of a stock solution of 10 µg carrier gas was helium, with a flow rate of 0.5 mL min .
1
−
mL ) at 37mC in teflon-capped glass tubes. After 2 h Samples were injected onto the column by split injection
the samples were centrifuged at 10000 g for 5 min and (split ratio l 1:10) and an injection port temperature of
the supernatant extracted as described above. In control 200mC. The oven temperature was held isothermally at
samples, β-glucuronidase was replaced by buffer. To 90mC. The limit of quantification for R-(k) and S-(j)-
test a possible stereo-conversion of both enantiomers in carvone in plasma and urine samples was 20p3.23 ng
1
1
−
−
urine samples under storage conditions, drug-free urine mL and 20p2.87 ng mL , respectively, by spiking

640
Walter Jager et al
drug-free plasma and urine with the enantiomers to give WinNonlin (vers. 1.5, Scientific Consulting, USA),
1
−
final concentrations of 10, 15, 20, 25 and 30 ng mL
where AUC represents the area under the concentra-
(n l 5). The injection volume was 1.5 µL. The analysed tion–time curve from 0 to 100 min using the linear
peaks were well separated from the peaks of the internal trapezoidal rule. Results are expressed as the meanps.d.
standard piperitone with no overlapping matrix peaks The significance of differences (P ! 0.01) was evaluated
(retention times for S-(j)-piperitone, R-(k)-piperi- by the Wilcoxon test.
tone, R-(k)-carvone, S-(j)-carvone, 4R,6S-(k)-car-
veol, 4S,6R-(j)-carveol, 4S,6S-(j)-carveol and 4R,
6R-(k)-carveol were approximately: 19.9, 23.1, 25.7,
26.3, 31.9, 33.5, 41.0 and 42.6 min, respectively).
Results and Discussion
The plasma concentrations of R-(k)- and S-(j)-car-
vone following separate topical application at a dose of
Data analysis
300 mg are shown in Figure 1. Both enantiomers rapidly
penetrated the skin and measurable blood levels could
The concentration–time curves of R-(k)- and S-(j)-
already be detected 10 min after dosing. At all sampling
time points the S-(j)-carvone concentrations were at
least 2 times higher than those for the R-(k) enantiomer
carvone in plasma samples were adjusted to the data sets
via nonlinear iterative least-square regression analysis.
Curve modelling was performed using a two-compart-
ment open pharmacokinetic model with the program
1
−
(Cmax, 88.0 and 23.9 ng mL , respectively), resulting
A
250000
A
1·25
R-(–)-Carvone
4R,6S-(–)-Carveol
4R,6S-(–)-Carveol-glucuronic acid
200000
150000
100000
50000
0
1·00
0·75
0·50
0·25
0·00
0
10
20
30
40
50
Retention time (min)
0
4
8
12
16
20
24
Time after administration (h)
250000
B
B
1·25
1·00
0·75
0·50
0·25
0·00
S-(+)-Carvone
200000
150000
100000
50000
0
0
10
20
30
40
50
Retention time (min)
Figure 3 Representative chiral GC chromatogram of a β-glucuro-
nidase pretreated urine sample after the topical application of R-(k)-
carvone (A) or S-(j)-carvone (B) to a healthy male subject. (k)-C,
0
4
8
12
16
20
24
Time after administration (h)
R-(k)carvone; (j)-C, S-(j)-carvone; R-IST, R-(k)-piperitone; Figure 4 Cumulative urinary excretion after the topical application
S-IST, S-(j)-piperitone; (k)-M, 4R,6S-(k)-carveol; (j)-M, 4S, of 300 mg of R-(k)- and S-(j)-carvone to healthy subjects. Data are
6S-(j)-carveol.
meanps.d., n l 4.

641
Absorption and stereoselective metabolism of carvone
R-(–)-Carvone
4R,6S-(–)-Carveol
4R,6S-(–)-Carveol-glucuronic acid
S-(+)-Carvone
4S,6S-(+)-Carveol*
Figure 5 The proposed metabolic pathway of R-(k)- and S-(j)-carvone in healthy subjects, administered as a single topical application of
300 mg. P450, cytochrome P450 system; UDPGT, UDP-glucuronosyl transferase. *Only found in human liver microsomes.
in a 3.4-fold higher AUC0–100 min(5420 and 1611 ng min ents. Surprisingly, pre-incubation of plasma samples
1
−
mL ) (Table 1). The elimination of R-(k)- and with β-glucuronidase did not reveal the formation of
S-(j)-carvone from the plasma was best described by either 4R,6S-(k)- or 4S,6S-(j)-carveol.
a two-compartment open model exhibiting significantly
However, analysing urine samples after R-(k)- but
different distribution half-lives (t12α) of 7.8 and 19.4 min, not after S-(j)-carvone application revealed an ad-
respectively, but similar elimination half lives (t21β ; 33.5 ditional peak in the GC chromatogram with a retention
and 37.5 min, respectively). No statistical differences for time of approximately 31.9 min (Figures 3A and B).
+
the values of the absorption rate constant, ka, and for This peak exhibited M -ions at m\z 152 amu and main
the time to reach the peak concentration, Tmax, between fragment ions at m\z 109, 95, 91 and 84 amu, re-
1
1
−
−
the two enantiomers were found (2.3 h and 2.2 h , spectively, which is consistent with (k)-carveol using a
27.8 min and 32.4 min, respectively).
mass spectral library search (Adams 1989). The re-
We previously demonstrated in an in-vitro model that tention time for (k)-carveol was the same as the re-
R-(k)- and S-(j)-carvone are stereoselectively bio- tention time of an authentic standard of 4R,6S-(k)-
transformed by human liver microsomes to 4R,6S-(k)- carveol. The formation of 4S,6S-(j)-, 4R,6R-(k)- and
and 4S, 6S-(j)-carveol, respectively, whereas only 4S,6R-(j)-carveol, respectively, was below the detec-
4R,6S-(k)-carveol is further glucuronidated. To inves- tion limit. Parallel incubations of these urine samples
tigate possible glucuronidation of carveol in man, with β-glucuronidase revealed a pronounced increase of
plasma samples were further treated with β-glucuro- 4R,6S-(k)-carveol, indicating that this carvone metab-
nidase. Representative chromatograms of plasma olite is a substrate for UDT-glucuronosyl transferases
samples are shown in Figures 2A and 2B. The extent of (UGTs).
racemization was below the detection limit and R-(k)-
The cumulative excretion of native R-(k)- and S-
and S-(j)-carvone and the two isomers of the internal (j)-carvone eliminated into the urine during 24 h after
standard, R- and S-piperitone (R\S: 85\15) were base- exposure was low (1.2 and 1.3 %, respectively) whereby
line-resolved from other endogenous medium constitu- the highest concentrations were found in the first 4 h

642
Walter Jager et al
(Figure 4). The percentage of 4R,6S-(k)-carveol- and cantly different blood levels. Only R-(k)-carvone was
4R,6S-(k)-carveol glucuronide on total R-(k)-carvone metabolized to 4R,6S-(k)-carveol, which was further
urinary elimination was high and was calculated to be glucuronidated and eliminated into the urine. If it is
7.6 and 19.1%, respectively. As previous experiments in assumed that 4R,6S-(k)-carveol glucuronide, like many
rats showed carvone concentration in the liver was up to other conjugated metabolites, is preferably eliminated
7 times higher than in blood (data not shown), 4R,6S- into bile, the lower plasma levels of R-(k)-carvone
(k)-carveol glucuronide excretion into bile and faeces compared with S-(j)-carvone are mainly due to stereo-
may markedly exceed its excretion into urine and may selective biotransformation.
account for the decreased plasma levels of R-(k)-
carvone.
The lower excretion of 4R,6S-(k)-carveol into the
urine compared with 4R,6S-(k)-carveol glucuronide
correlates well with in-vitro data using human liver
microsomes, where we found the Km for 4R,6S-(k)-
carveol glucuronide formation to be about 7-times
higher than that for 4R,6S-(k)-carveol. We may also
explain the non-detectable amounts of 4S,6S-(j)-
carveol in human plasma and urine after S-(j)-carvone
administration, as the Km for 4S,6S-(j)-carveol for-
mation was significantly higher than that for 4R,
6S-(k)-carveol, indicating lower affinity to the en-
zyme(s). 4S,6S-(j)-Carveol glucuronide was not found
either in plasma or urine.
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Figure 5 gives an overview of the proposed stereo-
selective metabolism of R-(k)- and S-(j)-carvone in
healthy subjects.
The major metabolic pathway for R-(k)-carvone is
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The hydroxyl metabolite undergoes further conjugation
with glucuronic acid. As we have found previously,
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and 4S,6S-(j)-carveol formationand shall also identify
the UGT-isoenzymes involved in 4R,6S-(k)-carveol
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selectivity in transdermal penetration may also influence
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In conclusion, R-(k)- and S-(j)-carvone rapidly
penetrated the skin of healthy subjects leading to signifi-

643
Absorption and stereoselective metabolism of carvone