ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,

0066-4804/99/$04.000
Jan. 1999, p. 9699 Vol. 43, No. 1
Copyright 1999, American Society for Microbiology. All Rights Reserved.
Effect of Probenecid on the Renal Excretion Mechanism of a
New Carbapenem, DA-1131, in Rats and Rabbits
SO H. KIM,
1
WON B. KIM,
2
AND MYUNG G. LEE
1
*
College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742,
1
and Research
Laboratory, Dong-A Pharmaceutical Company, Ltd., 47 Sanggal-Ri, Kiheung-Up, Yongin-Si,
Kyunggi-Do 449-900,
2
Korea
Received 15 December 1997/Accepted 1 September 1998
The effects of probenecid, an anion transport inhibitor, on the renal excretion mechanism of a new anionic
carbapenem, DA-1131, were investigated after a 1-min intravenous infusion of DA-1131 at 100 mg/kg of body
weight to rabbits and 50 mg/kg to rats with or without probenecid at 50 mg/kg for both species. In control
rabbits, the renal clearance (CL
R
) of DA-1131 and the glomerular ltration rate based on creatinine clearance
(CL
CR
) were 6.14 2.09 and 2.26 0.589 ml/min/kg, respectively. When considering the less than 10% plasma
protein binding of DA-1131 in rabbits, renal tubular secretion of DA-1131 was observed in rabbits. The CL
R
of DA-1131 (3.87 0.543 ml/min/kg) decreased signicantly with treatment with probenecid in rabbits,
indicating that the renal tubular secretion of DA-1131 was inhibited by probenecid. However, in control rats,
the CL
R
of DA-1131 (5.80 1.94 ml/min/kg) was comparable to the CL
CR
(4.29 1.64 ml/min/kg), indicating
that DA-1131 was mainly excreted by glomerular ltration in rats. Therefore, it could be expected that the CL
R
of DA-1131 could not be affected by treatment with probenecid in rats; this was proved by a similar CL
R
of
DA-1131 with treatment with (6.93 0.675 ml/min/kg) or without (5.80 1.94 ml/min/kg) probenecid.
Therefore, the renal secretion of DA-1131 is a factor in rabbits but is not a factor in rats.
DA-1131, (1R, 5S, 6S) (2S, 4S)-2-[(E)-3-methansulfonyl-
amino-1-propenyl]pyrrolidine-4-ylthiol-6-[(R)-1-hydroxyethyl]-
1-methyl-1-carbapen-2-em-3-carboxylic acid (Fig. 1), is a new an-
ionic carbapenem antibiotic. DA-1131 has a broad antibacterial
spectrum for both gram-positive and gram-negative organisms
(12); DA-1131 is more active than imipenem-cilastatin and mero-
penem against Staphylococcus aureus, Klebsiella pneumoniae, En-
terobacter cloacae, Proteus mirabilis, and Pseudomonas aeruginosa.
Judging from the maximum velocity-to-Michaelis-Menten con-
stant (V
max
/K
m
) ratios, DA-1131 showed relatively greater resis-
tance than imipenem and meropenem to mouse, rat, rabbit, dog,
and human renal dehydropeptidase I (DHP-I) (unpublished
data); especially, the ratio of DA-1131 in the rabbit DHP-I was
1.5 and 4.3 times smaller than those of imipenem and mero-
penem, respectively. The V
max
/K
m
ratios of DA-1131, imipenem,
and meropenem in human DHP-I were 1.43, 6.54, and 2.42,
respectively. Therefore, meropenem is more stable than imi-
penem against human DHP-I but is less stable than DA-1131.
DA-1131 is also resistant to degradation by various types of -lac-
tamases (13). DA-1131 is now being evaluated in a preclinical
study.
The high-performance liquid chromatographic (HPLC)
analysis of DA-1131 in biological uids (20), stability, tissue
metabolism, tissue distribution, and blood partition of DA-
1131 (15), pharmacokinetics of DA-1131 in animals (19), in-
terspecies pharmacokinetic scaling of DA-1131 (17), and the
pharmacokinetics of DA-1131 in rats with uranyl nitrate-in-
duced acute renal failure (21), in rats with alloxan-induced
diabetes mellitus (18), and in rabbits with endotoxin-induced
pyrexia (16) have been reported by our laboratories. In a pre-
vious study (19), the plasma protein binding of DA-1131 in rats
and rabbits was less than 10%. The renal clearance (CL
R
) of
DA-1131 (5.14 to 5.62 ml/min/kg) after intravenous (i.v.) ad-
ministration of the drug at 20 to 200 mg/kg of body weight to
rabbits (19) was higher than the reported creatinine clearance
(CL
CR
) in rabbits, 3.12 ml/min/kg (5), indicating that active
renal secretion of the drug was observed in rabbits. The CL
R
of
DA-1131 (5.63 to 6.80 ml/min/kg) after i.v. administration of
the drug at 50 to 500 mg/kg to rats (19) was slightly higher than
the reported CL
CR
, 5.24 ml/min/kg (5), in rats, indicating that
renal tubular secretion of the drug was not considerable in rats.
In the several studies that have been conducted with other
carbapenem antibiotics, imipenem and meropenem were re-
ported to be eliminated almost exclusively by the kidney
through both glomerular ltration and tubular secretion (1, 8).
Probenecid, an anion transport inhibitor, increased the half-
lives of imipenem and meropenem by 30% or more due to the
inhibition of tubular secretion of the drugs (1, 6, 7).
The purpose of this paper is to report on the effects of
probenecid on the renal excretion mechanism of DA-1131 in
rats and rabbits.
MATERIALS AND METHODS
Chemicals. DA-1131 (as an HCl salt) was donated by the Research Laboratory
of Dong-A Pharmaceutical Company (Yongin, Korea). Probenecid was a prod-
uct of Sigma Chemical Company (St. Louis, Mo.). Ketamine was supplied by
Yuhan Research Center of Yuhan Corporation (Kunpo, Korea). Other chemi-
cals were of reagent grade or HPLC grade and were used without further
purication.
Animals. Male Sprague-Dawley rats of 8 weeks of age (weight, 270 to 310 g)
were purchased from Charles River Company (Atsugi, Japan). Male New Zea-
land White rabbits (weight, 1.75 to 2.50 kg) were purchased from the Korea
Laboratory of Animal Development (Seoul, Korea). The animals were housed in
a light-controlled room kept at a temperature of 22 1C and a humidity of 55%
10% (College of Pharmacy, Seoul National University, Seoul, Korea), with
food (Samyang Company, Seoul, Korea) and tap water provided ad libitum.
Pretreatment of animals. The carotid artery and the jugular vein of each rat
were cannulated with polyethylene tubes (Clay Adams, Parsippany, N.J.) while
the animals were under light ether anesthesia. Both cannulae were exteriorized
to the dorsal side of the neck and terminated with a long silastic tube (Dow
Corning, Midland, Mich.). Both silastic tubes were covered with a wire to allow
free movement of the rat. The exposed areas were surgically sutured. Each rat
was housed individually in a rat metabolic cage (Daejong Scientic Company,
* Corresponding author. Mailing address: College of Pharmacy,
Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu,
Seoul 151-742, Korea. Phone: 822-880-7855 or 822-880-7877. Fax: 822-
889-8693. E-mail: leemg@plaza.snu.ac.kr.
96
Seoul, Korea) and were allowed to recover from the anesthesia for 4 to 5 h
before the commencement of the experiment. They were not restrained at any
time during the study. Heparinized 0.9% NaCl injectable solution (20 U/ml), 0.3
ml, was used to ush each cannula to prevent blood clotting.
Each rabbit was anesthetized with 50 to 100 mg of ketamine (50 mg/ml) given
i.v. via the ear vein, and the carotid artery and the jugular vein were catheterized
with a silastic tube (Dow Corning). Each cannula terminated in a three-way
stopcock. The exposed areas were surgically sutured. Each rabbit was restrained
individually in a rabbit cage during the entire experimental period and was
allowed to recover from anesthesia for 4 to 5 h before the commencement of the
experiment. Urine samples were collected via a pediatric Foley catheter (5
French; Sewon Company, Seoul, Korea) introduced into the urinary bladder.
Approximately 3-ml aliquots of the heparinized 0.9% NaCl injectable solution
were used to ush each cannula.
i.v. administration of DA-1131 with or without probenecid to rabbits and rats.
Probenecid (dissolved in 0.5 N NaOH and then adjusted to pH 7.4 with saturated
KH
2
PO
4
) (23), 50 mg/kg, was infused over 1 min via the jugular vein (total
injection volume, approximately 1 ml) of the rabbits (treatment I; n 6) a half
hour before the i.v. infusion of DA-1131. The same volume of 0.9% NaCl
injectable solution was infused into control rabbits (treatment II; n 9). DA-
1131 (DA-1131 as an HCl salt was dissolved in 0.9% NaCl injectable solution),
100 mg/kg, was administered intravenously over 1 min via the jugular vein of each
rabbit in both groups. The total injection volume was approximately 1 ml.
Approximately 0.25 ml of blood was collected via the carotid artery at 0 (to serve
as a control), 1 (at the end of infusion), 5, 15, 30, 45, 60, 90, 120, 180, 240, and
360 min after the i.v. administration of DA-1131. Approximately 3 ml of the
heparinized 0.9% NaCl injectable solution was used to ush each cannula im-
mediately after each blood sampling. Blood samples were centrifuged immedi-
ately to reduce or minimize the potential blood storage effect (the change in
the plasma DA-1131 concentration due to the time that elapsed between collec-
tion and centrifugation of the blood sample mainly due to degradation) of
DA-1131 in plasma (15). A 50-l aliquot of each plasma sample was stored in a
70C freezer (Revco ULT 1490 D-N-S; Western Mednics, Asheville, N.C.)
until HPLC analysis of DA-1131 (20). At the end of 8 h, the urinary bladder was
rinsed twice with 20 ml of distilled water and 20 to 40 ml of air to ensure
complete recovery of the urine. The rinsings were combined with the urine
sample. After measuring the exact volume of the combined urine sample, two
0.1-ml aliquots of the combined urine sample were stored in a 70C freezer
(Revco ULT 1490 D-N-S) until HPLC analysis of DA-1131 (20) and the mea-
surement of the creatinine level. At the same time, as much blood as possible was
collected via the carotid artery and each rabbit was killed. After centrifugation,
an aliquot (1 ml) of plasma sample was stored in a 70C freezer (Revco ULT
1490 D-N-S) for measurement of the creatinine level.
Probenecid (the same solution used in rabbits), 50 mg/kg, was infused over 1
min via the jugular vein (total injection volume, approximately 1 ml) of the rats
(treatment III; n 10) a half hour before the i.v. infusion of DA-1131. The same
volume of 0.9% NaCl injectable solution was infused into control rats (treatment
IV; n 14). DA-1131 (the same solution used in rabbits), 50 mg/kg, was
administered intravenously over 1 min via the jugular vein of each rat in both
groups. The total injection volume was approximately 1 ml. Approximately 0.12
ml of blood was collected via the carotid artery at 0 (to serve as a control), 1 (at
the end of infusion), 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 min after the i.v.
administration of DA-1131. At the end of 8 h, the metabolic cage was rinsed with
20 ml of distilled water and the rinsings were combined with the urine sample. At
the same time, as much blood as possible was collected via the carotid artery and
each rat was killed by cervical dislocation. After centrifugation, plasma was
collected for measurement of the creatinine level. Blood and urine samples were
handled similarly to those in the studies with rabbits.
HPLC assay and measurement of creatinine levels. DA-1131 in biological
samples was analyzed within 7 days by the previously reported HPLC method
developed in our laboratories (17). The mobile phase, 0.015 M KH
2
PO
4
and
acetonitrile (9:1; vol/vol) with a pH of 5.0, was run through a reversed-phase
column at a ow rate of 0.8 ml/min, and the column efuent was monitored with
a UV detector set at 300 nm. The retention time of DA-1131 was approximately
8.0 min. The detection limits of DA-1131 in human plasma and urine and in rat
tissue homogenate were 0.1, 0.5, and 0.1 g/ml, respectively. The mean within-
day coefcients of variation of DA-1131 in human plasma and urine were 2.85%
(range, 1.76 to 5.04%) and 2.85% (range, 1.65 to 4.75%), respectively. The mean
between-day coefcients of variation for the analysis of the same samples on 3
consecutive days were 2.30 and 4.29% in human plasma and urine, respectively.
The concentrations of creatinine in the plasma and urine of rats and rabbits
were determined by Jaffes picrate method (without the deproteinization kinetic
method) with a Hitachi 747 Automatic Analyzer (Hitachi, Tokyo, Japan).
Pharmacokinetic analysis. The total area under the plasma concentration-
time curve (AUC) from time zero to time innity (AUC
0
) was calculated by
the trapezoidal rule-extrapolation method (14); this method uses the logarithmic
trapezoidal rule recommended by Chiou (2) for calculation of the area during
the phase of a declining level in plasma and the linear trapezoidal rule for the
phase of a rising level in plasma. The area from the last datum point to innity
was estimated by dividing the last measured concentration in plasma by the
terminal rate constant.
A standard method (11) was used to calculate the following pharmacokinetic
parameters: the time-averaged total body clearance (CL), the area under the rst
moment of the plasma concentration-time curve (AUMC), the mean residence
time (MRT), the apparent volume of distribution at steady state (V
SS
), and the
time-averaged CL
R
and nonrenal clearance (CL
NR
) (14). The following equa-
tions were used: CL dose/AUC, AUMC

t C
p
dt, MRT AUMC/AUC,
V
SS
CL MRT, CL
R
X
U()
/AUC, and CL
NR
CL CL
R
, where C
p
is the
concentration of DA-1131 in plasma at time t and X
U()
is the amount of
DA-1131 excreted in urine up to time innity (this was assumed to be equal to
the total amount excreted in 8 h, since DA-1131 was present at a level below the
detection limit in the urine collected thereafter).
The mean values of CL, CL
R
, and CL
NR
(4), V
SS
(3), and terminal half-life
(t
1/2
) (9) were calculated by the harmonic mean method.
The glomerular ltration rates in rats and rabbits were estimated by measuring
the CL
CR
. CL
CR
was calculated by dividing the total amounts of creatinine
excreted in urine over 8 h by the AUC of creatinine from time zero to 8 h
(AUC
08
; (the concentration of creatinine in plasma was measured 8 h after the
administration of the i.v. dose), assuming that the kidney function was stable
during the 8-h experimental period.
Statistical analysis. A P value of less than 0.05 was considered statistically
signicant by the t test between two means for unpaired data. All data are
expressed as the mean standard deviation.
RESULTS
Pharmacokinetics of DA-1131 after i.v. administration to
rabbits. After i.v. administration to rabbits, the plasma DA-
1131 concentrations declined rapidly for both treatments (Fig.
2), with mean t
1/2
s of 20.1 and 17.2 min for treatments I and II,
respectively (Table 1). The plasma DA-1131 concentrations
were signicantly higher in treatment I than those in treatment
II (Fig. 2), and this resulted in a signicant increase in the
AUC (13,900 versus 7,980 g min/ml), AUMC (391,000 ver-
sus 118,000 g min
2
/ml), and MRT (27.9 versus 14.4 min) for
DA-1131 in treatment I (Table 1). The CL (7.21 versus 12.5
ml/min/kg), CL
R
(3.87 versus 6.14 ml/min/kg), and CL
NR
(3.10
versus 5.86 ml/min/kg) of DA-1131 were signicantly slower in
treatment I (Table 1). However, the V
SS
and t
1/2
of DA-1131
and the total amount of unchanged drug excreted in urine over
8 h (X
U08
) were not signicantly different between the two
treatments (Table 1).
Pharmacokinetics of DA-1131 after i.v. administration to
rats. After i.v. administration to rats, the plasma DA-1131
concentrations declined rapidly for both treatments (Fig. 3),
with mean t
1/2
s of 14.5 and 15.7 min for treatments III and IV,
respectively (Table 2). The plasma DA-1131 concentrations
were not signicantly different between the two treatments
(Fig. 3). The pharmacokinetic parameters of DA-1131 listed in
Table 2 were not signicantly different between treatments III
and IV.
DISCUSSION
The signicant increases in AUC (74% increase) and
AUMC (231% increase) for DA-1131 in treatment I were due
to the signicantly slower CL of DA-1131 (42% decrease) in
treatment I (Table 1). In treatment I, the compensatory
changes in the clearances (CL
R
and CL
NR
) of DA-1131 were
not observed; both the CL
R
(37% decrease) and the CL
NR
(47% decrease) of DA-1131 were signicantly slower than
FIG. 1. Chemical structure of DA-1131.
VOL. 43, 1999 EFFECT OF PROBENECID ON DA-1131 RENAL EXCRETION 97
those in treatment II (Table 1). Therefore, the signicantly
slower CL of DA-1131 in treatment I could be due to the
signicantly slower CL
R
and CL
NR
of DA-1131 in treatment I
(Table 1). In treatment II, the glomerular ltration rate based
on the CL
CR
was 2.26 ml/min/kg (Table 1). When considering
the level of plasma protein binding of DA-1131 in rabbits (less
than 10% [16]) and the CL
R
of DA-1131 in treatment II (6.14
ml/min/kg [Table 1]), renal tubular secretion of DA-1131 was
observed in control rabbits. However, in treatment I, the CL
CR
of DA-1131 was 3.54 ml/min/kg and the CL
R
of DA-1131 (3.87
ml/min/kg) was signicantly slower than that in treatment II
(Table 1), indicating that the renal tubular secretion of DA-
1131 was inhibited by probenecid. The signicantly slower
CL
NR
of DA-1131 in treatment I could be due to the consid-
erably slower metabolism of DA-1131 in the rabbit kidney,
possibly by DHP-I; this could be at least partly due to the
increased plasma DA-1131 concentrations (Fig. 2) from the
inhibition of the active renal secretion of the drug by probe-
necid. The existence of a Michaelis-Menten type of hydrolysis
of DA-1131 in rabbit kidney DHP-I was studied; the V
max
and
K
m
of DA-1131 were 3.45 units/mg and 0.63 mM, respectively
(unpublished data). The slower CL
NR
of DA-1131 obtained
after treatment with probenecid was also obtained after treat-
ment with meropenem (1), imipenem (6), T-3761, a novel
uoroquinolone (10), and diprophylline (22).
In treatment IV, the CL
R
of DA-1131 (5.80 ml/min/kg) in
FIG. 2. Mean arterial plasma concentration-time proles of DA-1131 after a
1-min i.v. infusion of the drug at 100 mg/kg without (E; n 9) or with (F; n
6) probenecid at 50 mg/kg to rabbits. Bars represent standard deviations. , P
0.01; , P 0.001.
FIG. 3. Mean arterial plasma concentration-time proles of DA-1131 after a
1-min i.v. infusion of the drug at 50 mg/kg without (E; n 14) or with (F; n
10) probenecid at 50 mg/kg to rats. Bars represent standard deviations. Each
point was not signicantly (P 0.05) different.
TABLE 1. Pharmacokinetic parameters of DA-1131 after a 1-min
i.v. infusion of the drug at 100 mg/kg to rabbits with (treatment I)
or without (treatment II) the administration
of probenecid at 50 mg/kg
a
Parameter
Treatment I
(n 6)
Treatment II
(n 9)
t
1/2
(min) 20.1 7.65 17.2 5.19
AUC (g min/ml)
b
13,900 1,510 7,980 2,000
AUMC (g min
2
/ml)
b
391,000 92,500 118,000 47,300
MRT (min)
b
27.9 4.01 14.4 3.79
CL (ml/min/kg)
c
7.21 0.782 12.5 4.29
CL
R
(ml/min/kg)
c
3.87 0.543 6.14 2.09
CL
NR
(ml/min/kg)
c
3.10 0.911 5.86 2.85
CL
CR
(ml/min/kg)
c
3.54 1.23 2.26 0.589
V
SS
(ml/kg) 200 21.7 176 47.5
X
U 08
(% of i.v. dose) 54.8 9.28 50.3 9.80
a
Values are means standard deviations.
b
P 0.001.
c
P 0.05.
TABLE 2. Pharmacokinetic parameters of DA-1131 after a 1-min
i.v. infusion of the drug at 50 mg/kg to rats with (treatment III)
or without (treatment IV) the administration
of probenecid at 50 mg/kg
a
Parameter
Treatment III
(n 10)
Treatment IV
(n 14)
t
1/2
(min) 14.5 1.66 15.7 2.47
AUC (g min/ml) 3,850 272 4,000 951
AUMC (g min
2
/ml) 46,500 8,020 48,700 14,600
MRT (min) 12.0 1.65 12.2 2.32
CL (ml/min/kg) 13.0 0.903 12.5 3.09
CL
R
(ml/min/kg) 6.93 0.675 5.80 1.94
CL
NR
(ml/min/kg) 5.99 0.653 6.26 2.05
CL
CR
(ml/min/kg) 4.97 2.13 4.29 1.64
V
SS
(ml/kg) 154 20.4 147 53.8
X
U 08
(% of i.v. dose) 53.6 3.70 48.8 8.71
a
Values are means standard deviations.
98 KIM ET AL. ANTIMICROB. AGENTS CHEMOTHER.
rats was not signicantly different from the CL
CR
(4.29 ml/min/
kg; Table 2), indicating that DA-1131 was excreted in urine
mainly via glomerular ltration in rats. Therefore, it was ex-
pected that the CL
R
of DA-1131 could not be affected by
treatment with probenecid, and this was proved by the insig-
nicant differences in the CL
R
of DA-1131 (6.93 versus 5.80
ml/min/kg) between treatments III and IV (Table 2). Note that
the percentage of the i.v. dose of DA-1131 excreted in bile as
unchanged drug over 8 h after i.v. administration of the drug at
200 mg/kg to six rats was very low; the value was 1.76% (19).
The data presented above indicate that the contribution of the
biliary excretion of DA-1131 to CL
NR
of DA-1131 in rats
seemed to be minor. Therefore, the CL
NR
listed in Table 2
could represent the metabolic clearance of DA-1131 in rats.
In conclusion, the renal tubular secretion of DA-1131 was
inhibited by probenecid in rabbits, but the effect of probenecid
was negligible in rats. Therefore, the renal secretion of DA-
1131 is a factor in rabbits but is not a factor in rats.
ACKNOWLEDGMENTS
This work was supported in part by the Korea Ministry of Science
and Technology (HAN Project), 19951996.
We thank Hae-ran Moon (Green Cross Reference Laboratory,
Seoul, Korea) for the measurement of creatinine levels in plasma and
urine.
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