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Antimicrobial Agents and Chemotherapy, March 2000, p. 578-582, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Pharmacokinetics and Safety of Ascending Single Doses of
DZ-2640, a New Oral Carbapenem Antibiotic, Administered to Healthy
Japanese Subjects
Makoto
Tanaka,1,*
Kinuyo
Kato,1
Hideo
Hakusui,1
Yoichi
Murakami,2
Kenichi
Sato,2
Yasushi
Ito,3 and
Keiji
Kawamoto4
Drug Metabolism and Analytical Chemistry
Research Laboratory,1 New Product
Research Laboratories I,2 Global Medical
Planning Department,3 and Medical
Development Department I,4 Daiichi
Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo 134-8630, Japan
Received 6 July 1999/Returned for modification 12 September
1999/Accepted 24 November 1999
 |
ABSTRACT |
DZ-2640 is the ester-type oral carbapenem prodrug of an active
parent compound, DU-6681. The pharmacokinetics and safety of DU-6681
were investigated in six studies after oral administration of a single
dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted
state. The same volunteers received the drug at a dose of 100 mg in the
fasted and fed states to examine the effect of food intake on the
bioavailability of DZ-2640. The concentrations of DU-6681 in plasma and
urine were determined by a validated high-performance liquid
chromatography method and a bioassay. A good correlation between both
methods was seen, indicating an absence of major active metabolites.
The mean maximum concentrations of DU-6681 in plasma
(Cmax) ranged from 0.263 µg/ml (25-mg dose)
to 2.489 µg/ml (400-mg dose) and were reached within 1.5 h
following drug administration. After reaching the
Cmax, plasma DU-6681 concentrations declined in
a monophasic manner, with a half-life of 0.47 to 0.89 h. The area
under the concentration-time curve (AUC) and
Cmax increased almost linearly with the dose up to the 200-mg dose. The AUC and Cmax increased
less than proportionally after administration of the 400-mg dose,
suggesting a reduction in drug absorption. The plasma protein binding
of DU-6681 was in the range of 23.3 to 25.6%. The cumulative urinary
recoveries (0 to 24 h) were in the range of 31.9 to 44.9%. The
AUC was slightly but statistically significantly reduced by food
intake. However, the Cmax, half-life, and
recovery in urine were not affected by food intake. The renal clearance
(402 to 510 ml/min) was much greater than the mean glomerular
filtration rate (ca. 120 ml/min), which indicated active tubular
secretion of the drug. A mild transient and moderate diarrhea was
observed in two of six volunteers in the study with a single dose of 25 mg. Mild soft stools were observed in two of six volunteers who
received a 400-mg dose of the drug.
| |
INTRODUCTION |
DZ-2640 is a new oral
carbapenem antibiotic with a dihydropyrroloimidazole ring as a side
chain and is a pivaloyloxymethyl (POM) ester prodrug of
(4R, 5S,
6S)-3-[[(6S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(DU-6681, the active parent drug). The bioavailability of DU-6681 was
greatly improved by esterification of the carboxy group at the C-2
position of the carbapenem ring with POM. DZ-2640 is believed to be
hydrolyzed by nonspecific esterases in the intestinal tracts of humans
to produce DU-6681, pivalic acid, and formaldehyde in a manner similar
to that for other prodrugs (1-3, 6). DU-6681 has a high
degree of in vitro activity against a broad spectrum of gram-positive
and gram-negative organisms (4). The chemical structures of
DZ-2640 and DU-6681 are shown in Fig. 1.
This paper describes the single-dose safety and pharmacokinetics of
DU-6681 following oral administration of single ascending doses of
DZ-2640 (25 to 400 mg) as part of the clinical evaluation of this drug.
| |
MATERIALS AND METHODS |
Chemicals and reagents.
DU-6681,
(4R,5S,6S)-3-[[(6S)-6,7-dihydro-5H-pyrrolo[1,2 - a]imidazol - 6 - yl]thio] - 6 - [(1R) - 1 - hydroxyethyl] - 4 - methyl - 7 - oxo - 1 - azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid, was synthesized by Daiichi Pharmaceutical Co. (Tokyo, Japan). Acetonitrile and methanol were high-performance liquid chromatography (HPLC)-grade solvents (Kanto Chemical, Tokyo, Japan).
3-(N-Morpholino)propanesulfonate (MOPS) was purchased from Sigma (St.
Louis, Mo.). All other chemicals were of analytical reagent grade and
were used without further purification. Purified water from a Milli-Q
system (Waters Associates, Millipore, Milford, Mass.) was used.
Study design.
The pharmacokinetics and safety of a single
oral dose of DZ-2640 were investigated in healthy male Japanese
volunteers who gave their written informed consent prior to
commencement of the study. The study was conducted in accordance with
the principles of the Declaration of Helsinki and also in accordance
with good clinical practices in Japan and International Conference on
Harmonization guidelines. This study was conducted at the New Medical
Research System Clinic (Tokyo, Japan). The study protocol and volunteer information document were reviewed and approved by an institutional review board. Forty-five subjects were recruited from the NS Clinic Volunteer Panel and entered the study. The subjects were screened according to the study's inclusion and exclusion criteria 2 weeks before dosing. The subjects who were finally selected on the basis of
physical examination and clinical laboratory findings on the day before
dosing were admitted to the clinic.
The study was conducted as a double-blind placebo-controlled study. The
study consisted of an escalation-dose regimen with
six doses ranging
from 25 to 400 mg (25, 50, 100 [fasted], 100
[fed], 200, and 400 mg). For each treatment group, six subjects
were given DZ-2640 and
three subjects were given placebo. The
subjects in each group ranged in
mean age from 21.6 to 22.9 years,
in mean height from 170.4 to 172.2 cm, and in mean body weight
from 59.3 to 64.8
kg.
The subjects had fasted from 2100 h on the previous day and while
sitting were dosed orally with 150 ml of water at 0900 h,
with a
2-min interval between every two subjects. Subjects were
not allowed to
lie supine for 1 h after dose administration except
during
performance of study procedures. Lunch was provided 4 h
after
dosing, but water was allowed ad libitum. The same subjects
received
the drug at a dose of 100 mg in the fasted and fed (a
standard
breakfast was given prior to dosing) states to examine
the effect of
food intake on the bioavailability of DZ-2640. One
subject accidentally
received placebo instead of DZ-2640 in the
fed state, and data for this
subject were excluded from the analysis
of the effect of food intake.
The washout phase between two treatments
was 3 weeks. The standard
breakfast consisted of two rolls (80
g), margarine (10 g), cheese (25 g), orange juice (100 ml), a
medium boiled egg (50 g), and low-fat milk
(150 ml). This breakfast
contained 27 g of protein, 27 g of
fat, and 96 g of
carbohydrate.
Each subject was assessed by the principal investigator to ensure that
he was fit and well prior to discharge from the clinic.
The subjects
returned to the clinic at approximately 7 days after
dosing for
poststudy assessment which included tests for blood
pressure, heart
rate, body temperature, electrocardiogram, and
laboratory findings.
Subjects were not allowed to take any medication
without an
investigator's permission until poststudy
assessment.
Sample collection.
Blood samples of 5 ml were collected in
heparinized containers at predosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h after oral administration of
DZ-2640. The blood samples were immediately centrifuged at
2,000 × g for 10 min to separate the plasma. The
separated plasma (2.0 ml) was transferred to a polypropylene tube and
was diluted with 1 M MOPS buffer (pH 7.0; 2.0 ml) to stabilize the
DU-6681. After dilution, the plasma sample was immediately frozen in a
dry ice-ethanol bath and was stored at 
80°C until analysis.
Urine samples were collected from
12 to 0, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 h after drug administration.
The urine
samples were kept at 2 to 4°C during the sampling interval.
The total
weight of each sampling interval was recorded, and the
total volume was
calculated by assuming that the specific gravity
of urine was 1.0. The
urine sample (20 ml) was transferred to
a polypropylene tube and was
diluted with 1 M MOPS buffer (pH
7.0; 20 ml) to stabilize the DU-6681.
After dilution, the urine
sample was immediately frozen in a dry
ice-ethanol bath and was
stored at
80°C until
analysis.
Plasma protein binding.
The plasma protein binding of
DU-6681 was determined ex vivo by an ultrafiltration method
(Centrifree; Grace Japan, Tokyo, Japan). The binding study was
conducted with plasma samples obtained from the volunteers at three
time points (2, 4, and 8 h after dosing) in the 200-mg dose study.
The concentration of unbound drug in the ultrafiltrate was measured.
DU-6681 did not show significant adsorption to the membrane. The
unbound fraction (FU) in plasma was calculated as the concentration in
the filtrate divided by the original concentration in plasma. The
plasma protein binding rate was calculated as (1 FU) × 100.
Analytical methods.
All drug assays were performed by
Daiichi Pharmaceutical Co. Ltd. in the Drug Metabolism and Analytical
Chemistry Research Laboratory, Tokyo, Japan. The concentrations of
DU-6681 in plasma and urine were determined with the use of a
modification of a column-switching semi-microcolumn HPLC method as
previously reported by Tanaka and Kato (5).
Briefly, human plasma diluted with an equal volume of 1 M MOPS buffer
(pH 7.0) was filtered through an Ultrafree-MC (10,000
NMWL; Millipore,
Bedford, Mass.) by centrifugation at 5,000 ×
g for 90 min at 4°C. The resulting filtrate was injected without
further
cleanup onto the HPLC system. Precolumn packed with Inertsil
ODS-3 (35 by 1.5 mm [inner diameter]; GL Science, Tokyo, Japan)
was used to
remove interfering endogenous substances in plasma.
Following online
solid-phase sample cleanup with a column-switching
device, the analyte
was chromatographed on a reversed-phase analytical
column, Inertsil
ODS-3 (250 by 1.5 mm [inner diameter]; GL Science),
with a mixture of
5 mM phosphate buffer (pH 6.5) containing 1
mM tetrabutylammonium
bromide and acetonitrile (80:20; vol/vol)
as the analytical mobile
phase at a flow rate of 0.1 ml/min.
Human urine diluted with an equal volume of 1 M MOPS buffer (pH 7.0)
was directly injected onto the HPLC system. Precolumns
packed with
LiChrosorb NH
2 (10 by 4.0 mm [inner diameter]; Merck,
Darmstadt, Germany) were used for sample pretreatment. A short
intermediate column, Inertsil ODS-3 (35 by 1.5 mm [inner diameter];
GL Science), was placed between the precolumn and the analytical
column
to minimize the loss of separation efficiency. Following
online
solid-phase sample cleanup with a column-switching device,
DU-6681 was
chromatographed on a reversed-phase analytical column,
Inertsil ODS-3
(150 by 1.5 mm [inner diameter]; GL Science), with
a mixture of 100 mM phosphate buffer (pH 6.5) and acetonitrile
(94:6; vol/vol) as the
analytical mobile phase at a flow rate
of 0.1 ml/min.
DU-6681 was detected by monitoring the column effluent with UV light at
a wavelength of 300 nm, which resulted in the limit
of quantitation of
0.016 µg/ml of plasma and 0.21 µg/ml of urine.
Calibration curves
were linear in the range of 0.016 to 7.64 µg/ml
in plasma and 0.21 to
101 µg/ml in urine. The intra- and interday
accuracy and precision of
the assay for DU-6681 in plasma were
<8% at concentrations above
0.016 µg/ml. At the quantitation limit
of 0.016 µg/ml, the method
showed an acceptable precision and
accuracy (<16%). The intra- and
interday accuracy and precision
of the assay for DU-6681 in urine were
<11% at concentrations
above 0.21 µg/ml. At the quantitation limit
of 0.21 µg/ml, the
method showed an acceptable precision and accuracy
(<9%). The
validity of the concentration results was verified by
assaying
quality control samples produced from blank plasma and urine
spiked
with known concentrations of DU-6681.
Additionally, concentrations in plasma and urine were determined by the
thin-layer paper disk method with
Bacillus subtilis ATCC
6633 as the test strain. The limit of quantification was
0.10 µg/ml.
To assess the comparability of the bioassay and the
HPLC method and to
detect the activities of potential microbially
active metabolites
relevant in humans, the concentrations determined
by both methods were
correlated.
Pharmacokinetic and statistical analyses.
The software used
for the pharmacokinetic analysis was TopFit (7), which was
run on an International Business Machines-compatible personal computer.
The pharmacokinetic parameters were determined by a model-independent
method. The elimination rate constant (
z) was
determined by least-squares regression of the logarithm of the
concentration in plasma with time over the terminal phase. The
half-life (t1/2) was calculated as
0.693/z. The maximum concentration in plasma
(Cmax) and the time required to reach
Cmax (Tmax) were read
from the observed values. The area under the concentration-time curve
(AUC) was determined to the last quantifiable concentration in plasma
by using the linear trapezoidal rule and was extrapolated to infinity
by using the terminal-phase rate constant. The mean residence time
(MRT) was calculated as the ratio of the area under the first moment
curve from time zero to infinity (AUMC0-
) to the AUC
from time zero to infinity (AUC0-). The apparent
total body clearance (CL/F) was calculated by using the equation
CL/F = dose/AUC0-.
The cumulative excretion of DU-6681 over 24 h
(
Xu0-24) was calculated in each study and
was expressed as a
percentage of the dose given. The renal clearance
(CL
R) was calculated
as [
X]/AUC from 0 to
24 h (AUC
0-24), where [
X] is the amount
of DU-6681 excreted in urine from 0 to 24 h after oral
dosing.
For statistical comparison of the pharmacokinetic parameters obtained
in the fasted state and those obtained in the fed state,
the Wilcoxon
signed rank test was used, with a
P value of 0.05
given as
the minimal level of significance. To evaluate the correlation
between
the doses ranging from 25 to 400 mg and the resulting
AUC and
Cmax, linear regression analysis was performed.
All data
are expressed as means ± standard deviations
(SDs).
| |
RESULTS |
Safety.
DZ-2640 given as a single oral dose ranging from 25 to
400 mg in the fasted state and 100 mg after a meal was safe and well tolerated. All 45 subjects completed the whole study, and there was no
clinically significant changes in findings from physical examinations,
vital signs, clinical laboratory findings, or electrocardiograms.
In the study with the 25-mg dose, one case of mild transient diarrhea
and one case of moderate diarrhea were observed in two
of six subjects
who received DZ-2640. At the 400-mg dose, two
of six subjects
experienced mild soft stools. All the other adverse
events were judged
to be not related to the DZ-2640
treatment.
Single-dose pharmacokinetics.
The mean concentrations of
DU-6681 from the plasma-versus-time profiles obtained after oral
administration of a single dose of DZ-2640 (25, 50, 100, 200, and 400 mg as DU-6681) to fasted male Japanese volunteers are shown in Fig.
2. The results of the noncompartmental
pharmacokinetic analysis derived from the concentrations in plasma and
urine are summarized in Table 1. The
absorption of DZ-2640 from the empty gastrointestinal tract was rapid,
and Cmax values of 0.263, 0.679, 0.999, 2.025, and 2.489 µg/ml of plasma appeared 1.00 to 1.42 h after oral
administration. After Cmax was reached, the
plasma drug level decreased monophasically, with elimination
t1/2s of 0.47 to 0.89 h. The
t1/2s proved to be slightly longer at higher
doses. The correlations between the administered doses (25 to 400 mg)
and the resulting AUC and Cmax are shown in Fig.
3. The correlation coefficients for AUC
and Cmax were 0.936 and 0.855, respectively.
AUC0- and Cmax increased almost
proportionally with the dose up to the 200-mg dose. The AUC and
Cmax increased less than proportionally after administration of the 400-mg dose, suggesting a reduction in the level
of drug absorption.
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FIG. 2.
Mean concentration in plasma-time profiles for DU-6681
in fasted healthy male volunteers following administration of single
ascending doses of DZ-2640 ranging from 25 to 400 mg (HPLC data).
Error bars indicate SDs (n = 6).
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TABLE 1.
Pharmacokinetic parameters of DU-6681 after oral
administration of single doses of DZ-2640 to fasted healthy
male volunteersa
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FIG. 3.
Correlation between the administered doses (25 to 400 mg) and the resulting AUC (A) and Cmax (B).
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The urinary excretion of DU-6681 was very fast and was almost completed
up to 4 h after oral dosing. The cumulative urinary
excretion of
DU-6681 (collection period, 0 to 24 h) amounted to
34.9% ± 13.2%, 44.9% ± 7.3%, 37.5% ± 6.8%, 38.9% ± 9.5%, and 31.9%
± 5.1% of the dose after oral administration of single doses of
25, 50, 100, 200, and 400 mg, respectively (Fig.
4). Cl
R ranged
from 402 to
510 ml/min and remained almost constant as the dose
increased.
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FIG. 4.
Mean cumulative urinary excretion of DU-6681 in fasted
subjects following administration of single ascending doses of DZ-2640
ranging from 25 to 400 mg (HPLC data). Error bars indicate SDs
(n = 6).
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To investigate the effect of food on the pharmacokinetics of DU-6681
after intake of a light meal, DZ-2640 (100 mg) was given
to the six
volunteers who received the same dose in the fasted
state. The
concentration in plasma-time profiles of DU-6681 in
the fasted and fed
states are shown in Fig.
5. The food
intake
had no significant influence (
P > 0.05;
n = 5) on
Cmax,
t1/2,
and cumulative recovery in urine (0 to 24 h). There was a
significant
(
P < 0.05) reduction in the AUC for fed
subjects (1.565 ± 0.473
µg · h/ml) compared to that for
fasted subjects (1.713 ± 0.434
µg · h/ml) (Table
2).
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FIG. 5.
Mean concentration in plasma-time profiles of DU-6681 in
fasted and fed subjects after administration of a single oral dose of
100 mg. Error bars indicate SDs (n = 5).
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TABLE 2.
Effect of food on pharmacokinetics of DU-6681 after oral
administration of single 100-mg doses of DZ-2640 to healthy
male volunteersa
|
|
Plasma protein binding.
The plasma protein binding rates 2 and
4 h after oral administration of a single 200-mg dose were 25.6 and 23.3%, respectively. The concentrations of DU-6681 in plasma
filtrate 8 h after dosing were less than the limit of
quantitation, and the plasma protein binding rates could not be determined.
Bioanalytics.
The concentrations of DU-6681 in plasma and
urine were determined by a bioassay and an HPLC assay. The correlations
were excellent for both plasma and urine, with slopes of 1.033 and
1.051, respectively, and coefficients of correlation of 0.979 and
0.996, respectively. These data indicate an absence of major active metabolites.
| |
DISCUSSION |
In the present study DZ-2640 was safe and well tolerated
when it was administered as single oral doses ranging from 25 to 400 mg. No clinically relevant changes in vital signs, electrocardiograms, findings from physical examinations, or laboratory study values were
seen. Only a few adverse events were reported, and all were mild in
intensity; moderate diarrhea, however, occurred after the
administration of the lowest dose (25 mg).
DZ-2640 as the capsule formulation was found to be rapidly absorbed
from the empty gastrointestinal tract, as indicated by the
Tmaxs, which were achieved 1.00 to 1.42 h
after oral administration (Fig. 2). AUC and Cmax
increased almost linearly over the dose range of 25 to 200 mg (Fig. 3).
The AUC and Cmax increased less than
proportionally after administration of the 400-mg dose, with which
absorption of the drug was slightly delayed, resulting in a prolonged
Tmax. The cumulative urinary excretion of
DU-6681 tended to be lower after administration of the 400-mg dose.
This suggests that a reduction in the drug absorption rate and extent occurred with the 400-mg dose. DZ-2640 shows a high degree of solubility at acidic pH because it has a basic dihydropyrroloimidazole group as a side chain. However, DZ-2640 has a low degree of solubility at neutral pH, suggesting that the solubility of the drug in intestinal fluids is also low. The reduction in absorption might be explained by
this low degree of solubility of the drug. Another explanation might be
that DZ-2640 undergoes a carrier-mediated absorption which is saturated
at the 400-mg dose. However, the mechanisms of the intestinal
absorption of DZ-2640 are unknown. Further studies are needed to
elucidate the mechanisms. However, the reduction in
Cmax and AUC at the highest dose does not seem
to be of clinical significance. A similar tendency was also reported
for another ester-type prodrug of carbapenem, CS-834 (8).
Approximately 32 to 45% of the administered dose was recovered in
urine as DU-6681 up to 24 h after administration of a single oral
dose, which indicated that the bioavailability of DZ-2640 in
human volunteers would be at least greater than 30% (Fig. 4). CLR ranged from 402 to 510 ml/min, and ca. 25% of the
DU-6681 was bound to plasma proteins. Thus, the CLR of free
DU-6681 was much greater than the mean glomerular filtration rate (ca.
120 ml/min). These data indicate that active processes take place in
the urinary excretion of DU-6681. Nonrenal clearance accounted for
about two-thirds of the CL/F. The quantitative contribution of biliary
excretion and/or metabolic reactions to this process has not yet been
fully investigated.
The effect of food intake on the pharmacokinetics of DU-6681 was
investigated by comparing the pharmacokinetic parameters obtained after
administration of the single 100-mg dose in the fasted and fed states
(Fig. 5). Food intake slightly but statistically significantly
decreased the AUC; however, there was no significant difference in the
cumulative urinary excretion of DU-6681 over 24 h. Other
pharmacokinetic parameters showed no statistically significant
difference between the fasted and the fed states (Table 2). The
influence of food on the pharmacokinetics of DU-6681 was not considered
clinically significant.
In this study the bioassay and HPLC data showed an excellent
correlation, indicating that no significant concentrations of metabolites with noticeable antimicrobial activity seem to be present
in plasma and urine over the time interval after single-dose administration investigated. Thus, it was proven that the
concentrations measured by bioassay and HPLC are adequate for
assessment of the pharmacokinetics of DU-6681 in humans with respect to
pharmacological (antimicrobial) activity. However, HPLC was superior
because of its higher sensitivity and better selectivity with respect
to metabolites.
In conclusion, DZ-2640 was well tolerated after the administration of
single oral doses up to 400 mg. DZ-2640 was rapidly absorbed from a
capsule formulation and was hydrolyzed rapidly to the active parent
drug, DU-6681. DU-6681 was rapidly eliminated from the body, with
elimination t1/2s of 0.47 to 0.89 h.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Drug Metabolism
and Analytical Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. Phone: 81-3-3680-0151. Fax: 81-3-5696-8332. E-mail:
LDP04207{at}nifty.ne.jp.
| |
REFERENCES |
| 1.
|
Melegh, B.,
J. Kerner, and L. L. Bieber.
1987.
Pivampicillin-promoted excretion of pivaloylcarnitine in humans.
Biochem. Pharmacol.
36:3405-3409[CrossRef][Medline].
|
| 2.
|
Nakashima, M., and K. Kosuge.
1996.
Influence of multiple-dose administration of cefetamet pivoxil on blood and urinary concentrations of carnitine and effects of simultaneous administration of carnitine with cefetamet pivoxil.
Chemotherapy (Tokyo)
49:966-979.
|
| 3.
|
Nakashima, M.,
T. Uematsu,
T. Oguma,
T. Yoshida,
K. Mizojiri,
S. Matsuno, and S. Yamamoto.
1992.
Phase I clinical studies of S-1108: safety and pharmacokinetics in a multiple-administration study with special emphasis on the influence on carnitine body stores.
Antimicrob. Agents Chemother.
36:762-768[Abstract/Free Full Text].
|
| 4.
|
Tanaka, M.,
M. Hohmura,
T. Nishi,
K. Sato, and I. Hayakawa.
1997.
Antimicrobial activity of DU-6681a, a parent compound of novel oral carbapenem DZ-2640.
Antimicrob. Agents Chemother.
41:1260-1268[Abstract].
|
| 5.
|
Tanaka, M., and K. Kato.
1999.
Sensitive semi-microcolumn high-performance liquid chromatographic method for the determination of DU-6681, the active parent drug of a new oral carbapenem antibiotic, DZ-2640, in human plasma and urine using a column-switching system as sample clean-up procedure.
J. Chromatogr. B
724:73-82[CrossRef].
|
| 6.
|
Totsuka, K.,
K. Shimizu,
M. Konishi, and S. Yamamoto.
1992.
Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans.
Antimicrob. Agents Chemother.
36:757-761[Abstract/Free Full Text].
|
| 7.
|
Transwell, P., and J. Koup.
1993.
TopFit: a PC-based pharmacokinetic/pharmacodynamic data analysis program.
Int. J. Clin. Pharmacol. Ther. Toxicol.
31:514-520[Medline].
|
| 8.
|
Umemura, K.,
Y. Ikeda,
K. Kondo,
M. Nakashima,
H. Nagamura,
M. Hisaoka,
H. Nishino, and M. Tajima.
1997.
Safety and pharmacokinetics of CS-834, a new oral carbapenem antibiotic, in healthy volunteers.
Antimicrob. Agents Chemother.
41:2664-2669[Abstract].
|
Antimicrobial Agents and Chemotherapy, March 2000, p. 578-582, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Top
Abstract
Introduction
