Yonago Acta medica 2005;48:33–40

Racemic Ketamine and S(+)-Ketamine Concentrations
in Cerebrospinal Fluid after Epidural and Intravenous
Administration in Rabbits
Hiroshi Adachi, Yoshimi Inagaki, Naoto Okazaki and Yuichi Ishibe
Division of Anesthesiology and Critical Care Medicine, Department of Surgery, School of
Medicine, Tottori University Faculty of Medicine, Yonago 683-8504 JapanThe Pharmacokinetic characteristic of ketamine, particularly the shift from the epidural space to the cerebrospinal ﬂuid (CSF), is still unclear. Furthermore pharmacokinetic
differences between racemic ketamine and S(+)-ketamine are not clearly described whenadministered into the epidural space. We measured plasma and CSF concentrations ofracemic ketamine and S(+)-ketamine after 2 mg/kg intravenous or 2 mg/kg epidural injection in 32 rabbits, and calculated pharmacokinetic parameters by the moment analysis method. The elimination half time of S(+)-ketamine was signiﬁcantly shorter thanthat of racemic ketamine and the systemic distribution volume of S(+)-ketamine wassigniﬁcantly smaller than that of racemic ketamine in the CSF. Pharmacokinetic parameters in the CSF after epidural injection of racemic versus S(+)-ketamines were: maximum concentration, 0.4 ± 0.1 versus 0.6 ± 0.2 µg/mL (not signiﬁcant); time to maximum
concentration, 9.7 ± 2.1 versus 9.0 ± 3.4 min (not signiﬁcant); elimination half time, 127.1± 25.2 versus 89.3 ± 19.4 min (P = 0.005); area under the curve, 56.4 ± 6.4 versus 56.6
± 11.0 µg•mL/min (not significant); and distribution volume, 19463.5 ± 3266.1 versus
13613.3 ± 4895.2 mL (P = 0.014), respectively. When injected intravenously, there wasno significant difference in these parameters of the CSF between racemic and S(+)ketamines. Racemic ketamine passed easily through the blood brain barrier when administered intravenously. It also shifted to the CSF through the systemic circulation,even when they were administered epidurally. S(+)-Ketamine had similar movement as
racemic ketamine.
Key words: analgesia; cerebrospinal ﬂuid; epidural administratin;ketamine; pharmacokinetics

epidural ketamine on the intensity of somatic andvisceral pain (Subramaniam et al., 2001). One of
the major issues behind this debate is the uncertainty regarding pharmacokinetics, especially thetransfer of ketamine into the cerebrospinal fluid(CSF), that is, the pharmacokinetics of transfer

Ketamine has been used widely as a sole anesthetic
when injected intravenously and as an adjuvant
analgesic agent with local anesthetics when administered epidurally (Islas et al., 1985; Naguib et al.,
1986; Ravat et al., 1987). However, it is still debatable that the experimental and clinical effects ofAbbreviations: AUC, area under the curve; BBB, blood brain barrier; BP, blood pressure; Cmax, maxmam concentration; CSF, cerebrospinal ﬂuid; HPLC, high-performance liquid chromatography; HR, heart rate; T1/2β, elimination half life; Tmax, time to maximum concentration; Vdss, distribution volume33

H. Adachi et al.
Pentobarbital (Abbott, Chicago, IL), 50 mg/kg, wasadministered through a 24 G stabilized catheter
inserted into the ear vein to anesthetize the rabbit. Then, the rabbit was fixed in supine position
and a tracheostomy was performed. Anesthesia
was maintained with 1 to 2% sevoﬂurane in an airoxygen mixture (inspired oxygen concentration =0.4). The rabbit was ventilated mechanically at a
respiratory rate of 40 breaths/min and tidal volumeof 10 mL/kg using a ventilator for small animals(rodent ventilator model 683, Harvard Medical Instruments, Cambridge, MA).

from the epidural space to the CSF across the duramater and from the systemic circulation to the CSF
through the blood brain barrier (BBB). Pedraz etal. (1991) reported in the dog model that ketamine
easily crosses the dura mater due to its lipid solubility when administered epidurally. However, there
is a report that epidurally administered ketamine
does not work at a segmental action (Horiuchi
et al., 1991). Moreover, there are no reports of aspinal segmental action for epidural ketamine, although epidurally administered lipid-soluble drugs
such as fentanyl are known to produce apparent
spinal segmental actions (Dos Santos et al., 1996;
Schols et al., 1996; Bernards et al., 2003a; 2003b).
We hypothesized that epidurally administered ketamine is rapidly absorbed into the systemic circulation and shifts into the intrathecal space throughthe BBB. This will also explain the non-segmental
action of ketamine.
Racemic ketamine consists of 2 optical isomers, S(+)-ketamine and R(-)-ketamine and it
is known that analgesic and sedative actions of
the S(+)-ketamine is much stronger, resulting inwidely clinical use in Europe (Geisslinger et al.,
1991; Kharasch et al., 1992; Arendt-Nielsen et al.,
1996; Murata et al., 2000). However precise pharmacokinetic study has not be elucidated regarding
differences in S(+)-ketamine and R(-)-ketamines
when administered in the epidural space. If pharmacokinetic parameters of S(+)-ketamine andR(-)-ketamines are widely different, the local
action of epidural ketamines may be segregated.
To test these hypothesis, the pharmacokinetics ofketamine in the CSF were studied by intravenousand epidural administrations of racemeic and S(+)ketamines.

Preparation of the rabbit
A 24 G catheter was inserted into the right femoral
artery for blood sampling and for monitoring ofblood pressure (BP) and heart rate (HR). Anothercatheter was inserted into the right internal jugularvein for injection o f racemic ketamine or S(+)ketamine. Lactated Ringerʼs solution was infused
at a rate of 10 ml/kg/h. The rabbit was then turned
into prone position and a laminectomy was performed at either C2 or C3 level using the electric
scalpel and the drill. A 2 Fr catheter for collectionof the CSF was inserted after conﬁrming of the location of the arachnoid membrane according to themethod of Tiscot et al. (1995). The epidural space
was punctured in the epidural administration groupat the interspace between L5 and L6 with a 20 G
Touhy needle according to the method of Taguchi
et al. (1996) and an epidural catheter was advanced
to 3 cm within the epidural space.

Sample collection
After completion of the preparation, we put a
30-min interval to stabilize arterial blood pressure,heart rate and end-tidal carbon dioxide tension
within normal limits. The vital signs were continuously monitored and kept within the normal range
throughout the study period. Either racemic ketamine or S(+)-ketamine (Alexis biochemicals, Lausen, Switzerland) were administered at 2 mg/kg ina bolus through the epidural catheter in the epidural

Materials and Methods
Anesthesia
Female Japanese white rabbits weighting 2.6 to 3.5
kg were used. The whole experimental procedureusing the animals was approved by the Tottori
University institutional animal care committee.

34

Ketamine CSF levels after epidural administrationgroups and injected as a bolus dose via the internal
jugular vein in the intravenous groups. The arterial
blood (1.5 mL) and CSF (0.2 mL) were simultaneously collected with heparinized syringes at 1, 3,
5, 10, 15, 30, 60 and 120 min after administrationof the test drug. Both samples were centrifuged at
3000 rpm at 0˚C and the supernatant was stored at–80˚C until analysis. Indocyanine green pigment(0.5 ml) was injected through the epidural catheterto conﬁrm an adequate positioning of the epidural
catheter in randomly selected rabbits.

ketamine group, intravenous racemic ketaminegroup and intravenous S(+)-ketamine group was 3.0
kg, 3.0 kg, 2.9 kg and 2.8 kg, respectively. There
were no significant differences in homodynamic
parameters (HR and BP). Figure 1 shows thechanges in the plasma and the CSF concentrations
over time in both groups of racemic ketamine.
Figure 2 also shows changes of concentration overtime in both groups of S(+)-ketamine. Plasma
concentrations were significantly higher than the
CSF concentrations throughout our study period inboth racemic ketamine and S(+)-ketamine epidural

Measurement
2.5

Racemic ketamine and S(+)-ketamine concentrations in the plasma and CSF were measured byhigh-performance liquid chromatography (HPLC)(Shimadzu SPD-10A, SCL-10A, LC-10AD, PGU12A, CTO10A and CR-8A, Kyoto, Japan). Chromatographic conditions were as follows: mobile
phase, phosphate buffer:methanol:acetonitorile =
7:2:1; velocity of mobile phase, 1.2 mL/min; temperature, 45˚C; wavelength, 215 nm; and column,
phenilcolumn. Pharmacokinetic parameters, maximum concentration (Cmax), time to Cmax (Tmax),elimination half time (T1/2β), area under the curve(AUC) and distribution volume (Vdss) were calculated from the plasma and CSF concentrations ofboth racemic ketamine and S(+) ketamine by the
moment analysis method using a pharmacokinetics
data analysis software (PK Solutions, version 2.0,
Montrose, CO).

(µg/mL)

*
*
*
*

a

Concentration

2.0

1.5

Plasma
CSF

*

1.0

*

0.5

*

*

0

2.5

(µg/mL)*

Concentration

2.0

Statistics

1.5
1.0

*

0.5

Parametric data were analyzed by Studentʼs t-test.
A P value less than 0.05 was considered statistically signiﬁcant. All data were expressed as mean
± SD.

b

0

0

30

*
60

Time

*
90

120
(min)

Fig. 1. Time course of concentrations of racemic ketamine in plasma and CSF following a bolus injection of
2 mg/kg epidurally (a) and intravenously (b). Closed
squares represent plasma concentrations. Closed circles
represent CSF concentrations. Data are expressed asmean ± SD. These graphs represent concentration
curves before pharmacokinetic analyzing. *P < 0.05,
plasma concentration versus CSF concentration.

Results
There were no signiﬁcant differences in the mean
body weight among 4 study groups, and that for the
epidural racemic ketamine group, epidural S(+)-

35

H. Adachi et al.
Table 1. Pharmacokinetic parameters in epidural administration
PlasmaRacemic ketamine

S(+)-Ketamine

P value

1.4 ± 0.5
6.3 ± 2.8
106.4 ± 27.8
111.5 ± 22.87754 ± 2172
0.4 ± 0.1
9.7 ± 2.1
127.1 ± 25.2
56.4 ± 6.4
19463 ± 3266

2.1 ± 0.5
8.3 ± 2.8
85.3 ± 27.6
247.3 ± 61.92992 ± 1055
0.6 ± 0.2
9.0 ± 3.4
89.3 ± 19.4
56.6 ± 11.0
13613 ± 4895

0.016*
0.167
0.149< 0.0001*< 0.0001*
0.055
0.595
0.005*
0.958
0.014*

Cmax(µg/mL)
Tmax
(min)
(min)
T1/2β
AUC (µg•min/mL)
Vdss
(mL)
Cmax
(µg/mL)
Tmax
(min)
(min)
T1/2β
AUC (µg•min/mL)
Vdss
(mL)

CSF

Data are expressed as mean ± SD.
AUC, area under the curve; Cmax, peak concentration; CSF, cerebrospinal fluid; T1/2β, elimination half life;
Tmax, time to peak concentration; Vdss, distribution volume.
* P < 0.05 for intergroup comparison.

Concentration

3.0(µg/mL)

*
* *
2.5
*
2.0 *

a

groups. In intravenous groups, plasma concentrations of racemic ketamine were signiﬁcantly higher
than the CSF concentrations at the point of 1, 30, 60
and 120 min. Also plasma concentrations of S(+)ketamine were significantly higher than the CSF
concentration at the point of 1, 10, 15, 30, 60 and
120 min.

Plasma
CSF

*
*

1.5

*

1.0

Pharmacokinetic parameters

0.5

When these agents were administered epidurally, Cmax of racemic ketamine was significantly
smaller than that of S(+)-ketamine, AUC of racemic ketamine was signiﬁcantly smaller than that ofS(+)-ketamine and Vdss of racemic ketamine wassignificantly larger than that of S(+)-ketamine in
the plasma. In the CSF, T1/2β of racemic ketamine
was signiﬁcantly longer than that of S(+)-ketamine
and Vdss of racemic ketamine was significantly
larger than that of S(+)-ketamine (Table 1). On theother hand, when these drugs were injected intravenously, T1/2β of racemic ketamine was signiﬁcantly

0
2.5

Concentration

2.0(µg/mL)

1.5

*

1.0
0.5
0

b

*

0

*

*
30

*
60

Time

*
90

120
(min)

Fig. 2. Time course of concentrations of S(+)-ketamine in plasma and CSF following bolus injection of 2 mg/kg
epidurally (a) and intravenously (b). Closed squares represent plasma concentrations. Closed circles represent CSF
concentrations. Data are expressed as mean ± SD. These graphs represent concentration curves before pharmacokinetic analyzing. *P < 0.05, plasma concentration versus CSF concentration.

36

Ketamine CSF levels after epidural administration
Table 2. Pharmacokinetic parameters in intravenous administration
PlasmaCSF

Cmax(µg/mL)(min)
T1/2β
AUC (µg•min/mL)
Vdss
(mL)
Cmax
(µg/mL)
Tmax
(min)
(min)
T1/2β
AUC (µg•min/mL)
Vdss
(mL)

Racemic ketamine

S(+)-Ketamine

P value

2.4 ± 1.0
145.9 ± 56.6
87.8 ± 24.2
11666 ± 4043
0.6 ± 0.3
6.0 ± 2.6
143.6 ± 34.8
54.9 ± 16.620523 ± 4762

1.7 ± 0.4
87.6 ± 22.8
93.9 ± 17.2
7287 ± 1583
0.7 ± 0.2
5.6 ± 3.8
120.1 ± 36.4
56.9 ± 14.3
16064 ± 3925

0.123
0.017*
0.571
0.013*
0.625
0.829
0.207
0.797
0.060

Data are expressed as mean ± SD.
AUC, area under the curve; Cmax, peak concentration; CSF, cerebrospinal fluid; T1/2β, elimination half life;
Tmax, time to peak concentration; Vdss, distribution volume.
* P < 0.05 for intergroup comparison.

Table 3. Comparison of CSF concentrations of racemic ketamine and S(+)-ketamine between epidural and intravenous groups
PlasmaCSF

Cmax(µg/mL)
Tmax
(min)
T1/2β
(min)
AUC (µg•min/mL)
Vdss
(mL)
Cmax
(µg/mL)
Tmax
(min)
T1/2β
(min)
AUC (µg•min/mL)
Vdss
(mL)

Racemic ketamine

S(+)-Ketamine

P value

0.4 ± 0.1
9.7 ± 2.1
127.1 ± 25.0
56.4 ± 6.4
19463 ± 3266
0.6 ± 0.2
9.0 ± 3.4
89.3 ± 19.4
56.6 ± 11.0
13613 ± 4895

0.6 ± 0.3
6.0 ± 2.6
143.6 ± 34.8
54.9 ± 16.620523 ± 4762
0.7 ± 0.2
5.6 ± 3.8
120.1 ± 36.4
56.9 ± 14.3
16064 ± 3925

0.076
0.007*
0.294
0.814
0.612
0.302
0.081
0.053
0.966
0.288

Data are expressed as mean ± SD.
AUC, area under the curve; Cmax, peak concentration; CSF, cerebrospinal fluid; T1/2β, elimination half life;
Tmax, time to peak concentration; Vdss, distribution volume.
* P < 0.05 for intergroup comparison.

longer than that of S(+)-ketamine and Vdss of racemic ketamine in the plasma was signiﬁcantly larger
than that of S(+)-ketamine in the plasma (Table 2).
Tmax was signiﬁcantly shorter when administeredintravenously than when administered epidurally(P = 0.007) in the pharmacokinetic parameters on
the shift to the CSF of racemic ketamine (Table 3).
After completion of the experiments, the locationof epidural catheter tip was conﬁrmed by stainingof the epidural space from L1 to L6 level.

Discussion
The major findings were as follows: i) The CSF
concentrations of both racemic ketamine and S(+)ketamine approximated to their plasma concentrations 3 min after intravenous administration.
Thereafter their concentration curves over time in
the CSF were similar to those in the plasma. ii)
The CSF concentration of both racemic ketamineand S(+)-ketamine were significantly lower thantheir plasma concentration after epidural adminis-

37

H. Adachi et al.
tration. These ﬁndings indicate that intravenously
administered ketamine rapidly and massively shifts
into the CSF through the BBB. Furthermore epidurally administered ketamine is rapidly absorbed
into the systemic circulation through the epidural vessels and shifts into the CSF. Increase in the
CSF concentrations of racemic ketamine until 10
min after epidural administration is considered tobe conducted by the amount of ketamine, whichshifted to the CSF across the BBB and penetrated
into the CSF across the dura mater. As AUC of racemic ketamine in the plasma is signiﬁcantly larger
than that in the CSF (111.5 µg•min/mL in the plasma versus 56.4 µg•min/mL in the CSF, P < 0.0001),
amount of ketamine absorbed into the plasma fromthe epidural space is likely to be more than thatabsorbed directly into the CSF. Taking rapid shiftof racemic ketamine from the plasma to the CSF
into consideration, we propose that shift from theplasma to the CSF across the BBB may play an important role in increase of the CSF concentration of
racemic ketamine.
It has been still unclear how the intravenously
administered ketamine shifts to the CSF acrossthe BBB. Furthermore, our results demonstrated
that they shifted rapidly to the CSF across the BBB
after an intravenous bolus injection. Their CSF
concentrations approximated to their plasma concentrations 3 min after intravenous administration,
thereafter, their concentration curves over time in
the CSF were similar to those in the plasma. Thisis the ﬁrst report to indicate that both racemic ketamine and S(+)-ketamine rapidly get across the
BBB.
Horiuchi et al. (1991) reported that racemic
ketamine administered epidurally in rabbits showednone of the inhibition of somatosensory evokedeyelid microvibration produced by stimulation of
sciatic and ulnar nerves, concluding that racemic
ketamine administered into the epidural space did
not produce spinal segmental action. If racemic
ketamine penetrated into the CSF through the duramater and increased its concentration in the CSF
more than that in the plasma as mentioned previously, somatosensory evoked potential would be
inhibited by intrathecal racemic ketamine. There-

fore, racemic ketamine unlikely shifts into the CSF
through the dura mater in rabbits. Moreover, there
is no report on analgesic effect produced by epidural ketamine in dogs to our knowledge. Our results
and the above-mentioned phamacodynamic results
suggested that the direct penetration to the CSF
across the dura mater of racemic ketamine would
be less in rabbits than that in dogs previously described by Pedraz (Pedraz et al., 1991).
In the comparison of racemic ketamine with
S(+)-ketamine on pharmacokinetic analysis, S(+)ketamine showed a shorter elimination half timefrom the plasma and a smaller distribution volume
in the plasma than racemic ketamine. There wereno significant differences in pharmacokinetic parameters on the CSF between racemic ketamineand S(+)-ketamine. These findings suggest that
S(+)-ketamine is a beneficial drug for the patient
rather than racemic ketamine to get pharmacological action as well as racemic ketamine in the CSF
and to reduce the incidence of adverse effects whenadministered intravenously. S(+)-ketamine had
similar pharmacokinetic parameters to those of
racemic ketamine when administered epidurally.
The concentrations of S(+)-ketamine in the plasma
were significantly more than those in the CSF
throughout the study period. Its AUC in the plasma
also was larger than that in the CSF indicating that
S(+)-ketamine was absorbed to the plasma morethan to the CSF. We believed that S(+)-ketamine
administered epidurally shifted to the CSF acrossthe BBB rather than by direct penetration throughthe dura mater as well as racemic ketamine. Interestingly, S(+)-ketamine had a larger AUC anda smaller Vdss compared with racemic ketamine
when they had administered epidurally. This indicates that S(+)-ketamine is absorbed from the epidural space to the plasma more than racemic ketamine and attains to higher plasma concentration
than racemic ketamine, resulting in a signiﬁcantly
higher Cmax of S(+)-ketamine in the plasma than
racemic ketamine. S(+)-ketamine had a significantly shorter T1/2β and a smaller Vdss in the CSF
than racemic ketamine. This is the ﬁrst report that
demonstrated different pharmacokinetic characteristics between racemic ketamine and S(+)-ket-

38

Ketamine CSF levels after epidural administration

amine. The differences were probably elicited by
the difference in structures of racemic mixture andthe S(+)-isomer of ketamine. Fast disappearance
from the CSF and small drug distribution in the
CSF appears to decrease the intensity of adverse effect, suggesting that S(+)-ketamine is a preferable
agent to the patient rather than racemic ketamine
when administered epidurally.
We set study period on the basis of the resultsof previous study (Pedraz et al., 1991). However,actual elimination half times in the CSF after intravenous and epidural administration of racemic ketamine were longer than our study period (120 min).
The study period longer than 120 min would prolong the elimination half time and increase AUC.
However, addition of points for collecting samples
beyond 120 min after a bolus injection is not considered to affect our results on pharmacokinetic parameters because concentration curves of racemic
ketamine in the plasma and the CSF became very
gentle decline from 60 min after administration.
In conclusion, racemic ketamine administeredepidurally shifted into the plasma and passed easily
through the BBB. And same as racemic ketamine,
S(+)-isomer of ketamine were absorbed from theepidural space to the plasma significantly morethan to the CSF when administered epidurally.
Passage into the CSF across the BBB through thesystemic circulation may play a predominant rolein the shift of ketamine from the epidural space to
the CSF in rabbits.

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Acknowledgments: We are grateful to Professor
Keisuke Satoh, Division of Molecular Pharmacology,
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Received December 8, 2004; accepted January 7, 2005
Corresponding author: Yuichi Ishibe, MD

40