Design, synthesis, and evaluation of prodrugs of ertapenem

Article abstract of DOI:10.1021/ml400092n

Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3- dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.

Full text of DOI:10.1021/ml400092n

Letter
pubs.acs.org/acsmedchemlett
Design, Synthesis, and Evaluation of Prodrugs of Ertapenem
Sheo B. Singh,*,† Diane Rindgen,† Prudence Bradley,† Lovji Cama,† Wanying Sun,† Michael J. Hafey,†
Takao Suzuki,‡ Nengxue Wang,‡ Hao Wu,‡ Basheng Zhang,‡ Li Wang,‡ Chongmin Ji,‡ Hongshi Yu,‡
Richard Soll,‡ David B. Olsen,§ Peter T. Meinke,† and Deborah A. Nicoll-Griffith†
†Merck Research Laboratories, Rahway, New Jersey 07065, United States
‡Wuxi Apptec, Shanghai, People Republic of China
§Merck Research Laboratories, West Point, Pennsylvania 19486, United States
S
* Supporting Information
ABSTRACT: Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home
with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because
of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and
synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is
described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-
dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and
monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed
the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.
KEYWORDS: Ertapenem, carbapenem, antibiotics, prodrugs, ertapenem diethyl ester, intraduodenal dosing, ertapenem bis-pivoxyl,
ertapenem bis-lactone
arbapenems are some of the most effective lifesaving
plasma half-life, and the longer duration of action. Therefore,
we selected ertapenem for prodrug studies, which could lead to
a once daily oral carbapenem. The design, synthesis, and
evaluation of selected prodrugs of ertapenem are described
herein.
C
broad-spectrum antibiotics that are in clinical practice.1
They are administered by intravenous infusion in a hospital
setting. Once bacterial burden of a patient is reduced and the
symptoms are improved, the patient is generally sent home
with a noncarbapenem oral antibiotic. This sometimes causes a
challenge in patient compliance and elimination of residual
bacteria in patient often causing the patient to return to the
hospital. Carbapenem antibiotics are not orally absorbed due to
very high polarity. The polarity of these compounds can be
reduced by synthesis of lipophilic prodrugs. Surprisingly, not
much work has been reported on the prodrugs to allow oral
dosing of these antibiotics. Orapenem (tebipenem pivoxyl, 1) is
one exception. It is a pivaloxymethyl ester prodrug of
tebipenem (2) and is approved for clinical use in Japan.2−6
Ertapenem (3) is a member of the carbapenem class of
antibiotics that is broadly used worldwide. This is the only
carbapenem antibiotic that is dosed once daily.1,7,8 While the
core structures of ertapenem and tebipenem is common, they
are differentiated by the structure of their side chain
substituents at C-2. Tebipenem possesses a basic side chain
consisting of azetidino-thiazolidine, whereas ertapenem consists
of a prolyl-3-aminobenzoic acid. The latter functionalities of
ertapenem lead to higher protein binding (92−94%), longer
Ertapenem possesses four polar groups that could be
derivatized for prodrugs. We primarily focused our attention
on the ester prodrugs of the two carboxyl groups. We selected
prodrug moieties that are well precedented and are part of
approved drugs. One of the key attributes required for the
prodrugs was to have no or significantly attenuated antibacterial
activity. This could be accomplished by esterification of the C-3
carboxyl group. Thus, we chose to synthesize only diester and
bis-lactone prodrugs. The prodrug moieties that fit these
criteria are pivaloxymethyl (e.g., drug, adefovir dipivoxyl,
cefetamet pivoxil),9,10 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl
(e.g., lomesartan medoxomil, olmesartan medoxomil),9,11 ethyl
(e.g., xemilofiban),12 and lactone (e.g., lovastatin).13 We
incorporated concepts of these prodrug moieties and prepared
Received: March 5, 2013
Accepted: July 3, 2013
Published: July 3, 2013
© 2013 American Chemical Society
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a series of prodrugs. Four of these prodrugs (bis-pivaloxymethyl
(POM) ester (4), bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)
(medoxomil) ester (5), diethyl ester (6), and propyl-bis-lacone
(7)) are described herein.
The synthesis of bis-esters started with the protection of the
basic amine of the ertapenem by reacting ertapenem-sodium
(3-Na) with allyl chloroformate at a neutral pH to produce
allyloxycarbonyl intermediate 8, which was lyophilized as a
sodium salt and used without further purification. The reaction
pH was tightly controlled to neutral levels and the product was
used directly for the next step to prevent decomposition. The
disodium salt of 8 was bis-alkylated by reaction of two
equivalents of appropriate alkyl iodides to afford diesters 9a−
9c. The allyloxy carbamate protecting group was removed by
reacting 9 with phenylsilane catalyzed by tetrakis-
(triphenylphosphine) palladium (Scheme 1). The final prodrug
diesters were purified by reversed phase HPLC. These bis-
esters were synthesized in ∼20% overall yields and >96%
purity.
For the synthesis of ertapenem-propyl-bis-lactone (7),
allylcarbamate disodium salt of ertapenem (8) was reacted
with one equivalent of 1,3-diiodopropane to afford the
protected macrocyclic lactone 10, which was deprotected
with phenylsilane to furnish the final bis-lactone 7 (Scheme 2)
after reversed phase HPLC purification (∼15% yield and 97%
purity).
Scheme 2. Synthesis of Macrocyclic Ester Prodrugs of
a
Ertapenem
a
Scheme 1. Synthesis of Diester Prodrugs of Ertapenem
a
Reagents: (i) ICH2CH2CH2I, benzyltriethylammonium chloride,
DIEA, DMF, 40 °C, 4−18 h; (ii) Pd(PPh3)4, phenylsilane, DMF,
room temperature, 60 min.
All four compounds were tested for their stability in
phosphate buffer (pH 7), simulated gastric fluid (SGF) (pH
2.0), and simulated gastrointestinal fluid (FaSSIF, pH 6.5).
Samples were analyzed by LC−MS/MS. All four compounds
were stable in phosphate buffer and FaSSIF at 50 μM for
greater than 3 h. All prodrugs were unstable in SGF producing
over 25% β-lactam ring open decomposition products in 60
min.
All prodrugs were evaluated for the hydrolysis by rat, human,
dog, and monkey plasma to produce ertapenem. It is well-
known that rat plasma has additional esterases (e.g.,
carboxylesterases and cholinesterases) compared to higher
species.14 Higher mammalian species including humans express
many of these esterases in liver.15 It is expected that in vitro
hydrolysis of the prodrugs in the rat plasma may be more
pronounced than corresponding hydrolysis in the plasma of
other mammalian species. Therefore, any prodrug that is stable
a
Reagents: (i) allyl chloroformate, water, acetone, phosphate buffer
(pH 7), room temperature, 30 min; (ii) benzyltriethylammonium
chloride, DIEA, DMF, 40 °C, 4−18 h; (a) iodomethyl pivalate; (b) (5-
methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) iodide; (c) ethyl
iodide; (iii) Pd(PPh3)4, phenylsilane, DMF, room temperature, 10−30
min.
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ACS Medicinal Chemistry Letters
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in the rat plasma may not be suitable for further studies. For the
plasma hydrolysis experiments, the prodrugs (50 μM) were
incubated for 60 min, and the hydrolytic rate was determined
by measurement of the disappearance of the prodrug and
appearance of the ertapenem by sampling at 5, 15, 30, and 60
min. The analysis was performed by quantitative LC−MS/MS,
and the results are summarized in Table 1. Ertapenem was
stable in all plasmas tested.
polarity, and low logD (Table 2). This class of compound is
known to be highly unstable at low pH as evidenced by
Table 2. Calculated and Measured Properties of Tebipenem
Pivoxyl, Ertapenem, and Its Prodrugs
a
b
bc
,
compd #
MW
cPSA
clogD
cPapp
Papp
1
2
3
4
5
6
7
497.6
383.5
475.5
703.8
699.7
531.6
515.6
109
93
2
12
10.1
0.7
2.4
−5.9
3
5.2
1.8
7.2
6.7
6.9
8.2
156
187
205
134
134
0.5
Table 1. Results of the Plasma Hydrolysis of the Prodrugs
a
(4−7)
−0.7
2.9
13
% remaining prodrug and % conversion to the parent carbapenem
after 60 min
1.1
a
b
c
ACD + clogP at pH 7.4. 10−6 cm/s. LLC-PK1 cell line.
rat
human
dog
monkey
compd #
%R
%C
%R
%C
%R
%C
%R
%C
1
4
5
6
7
0
2
1
0
0
95
46
89
2
0
95
1
25
37
3
75
1
0
95
NT
58
0
significant instability of ertapenem and prodrugs in SGF.
Therefore, in order to develop a viable prodrug, the compounds
have to be dosed in a way that bypasses the stomach acid. This
can be achieved by enteric coated tablets/capsules. However, it
is rather difficult to enteric coat each compound in the
discovery phase not least because of the high amount of
compound requirement but also due to high formulation
investment. Therefore, an alternative dosing regimen that
bypasses the stomach was sought. Intraduodenal (ID) dosing
accomplishes this goal. Therefore, this approach was adopted
for the PK studies of ertapenem prodrugs in rats and dogs.
First, male Sprague−Dawley rats were ID dosed with
ertapenem (3), tebipenem (2), and tebipenem pivoxyl (1),
and data was compared with the data from IV and PO dosing.
While ertapenem showed dismal absorption by ID and PO
dosing (Table 3), the absorption was marginally better by ID
dosing. Surprisingly, no absorption difference was observed for
tebipenem pivoxyl whether dosed ID or PO (data not shown).
The comparison of calculated physical properties of ertapenem
(3), its prodrugs (4−7), tebipenem (2), and tebipenem pivoxyl
(1) are presented in Table 2. Tebipenem showed better
properties for oral absorption than ertapenem as defined by
lower molecular weight, lower polar surface area, and better
permeability (Table 2). These properties for tebipenem pivoxyl
appear to be more favorable for absorption and was reflected by
observed higher bioavailability (40−73%) in various species
including human.16 The calculated properties of the ertapenem
prodrugs (4−7) showed improvement over corresponding
properties of ertapenem but none of the prodrugs appears to be
as good as tebipenem pivoxyl, which proved to be the case with
dismal observed GI absorption in SD rats (Table 3). After
dosing of ertapenem prodrugs, we analyzed the plasma for
AUC of the dosed prodrug, ertapenem, and the two
monoesters as listed. The bioavailability (F%) was calculated
for ertapenem alone as well as for all ertapenem metabolites
and ertapenem, which is expressed as total absorption. The
total absorption was calculated by adding the AUC of
ertapenem, prodrug intermediates, and parent prodrugs. ID
dosing of prodrugs 4 and 5 in SD rats resulted in only 0.37%
and 0.77% ertapenem, respectively, in plasma indicative of poor
absorption of these compounds in rat and not due to poor
hydrolysis since no parent prodrug was detected. ID dosing of
the diethyl ester (6) in SD rats showed 4.98% ertapenem and
0.63% of 1:6 ratio of C-3 (6a) and benzoate (6b) monoesters
in the plasma.
36
1
NT
2
98
0
43
0
5
75
79
77
49
0
17
0
0
0
a
S = stable, R = remaining, C = conversion to ertapenem from 4-7 and
tebipenem from 3, and NT = not tested.
All four compounds rapidly disappeared in rat plasma within
5 min of incubation. However, only bis-medoxomil (5)
quantitatively produced ertapenem in 60 min. Bis-pivalox-
ymethyl ester (4) produced 46% ertapenem in 60 min in rat
plasma. Diethyl ester (6) and bis-lactone (7) did not produce
any ertapenem after 60 min incubation in the rat plasma.
Prodrug 5 was completely hydrolyzed by human plasma
affording quantitative conversion to ertapenem in 60 min. The
prodrug 5 was completely consumed in dog and monkey
plasma but formation of the ertapenem was only 43% and 58%,
respectively, in 60 min, while 95% diethyl ester 6 disappeared
by incubation in the human plasma after 60 min but no
ertapenem was formed. Compounds 6 and 7 showed significant
stability in dog and monkey plasma. Incubation of tebipenem
pivoxyl (1) in all four plasmas quantitatively produced
tebipenem in less than 15 min indicating significant C-2
substitution (ertapenem vs tebipenem) selectivity for the
hydrolysis by various plasma esterases.
Since many esterases are expressed only in the liver in the
higher species, it was important to complement plasma
hydrolysis studies of the selected compounds for hydrolysis
in the liver microsomal preparations and hepatocytes.
Incubation of the diethyl ester 6 in rat, human, dog, and
monkey liver microsomal preparations with or without
NADPH produced a mixture of 5−10% each of the ertapenem
(3) and mono benzoate ethyl ester (6b) and about 50% of the
C-3 ethyl ester (6a) in about 15 min. The rate of the hydrolysis
of 6 by human and dog hepatocytes was slower but most of the
parent was consumed in 60 min with major (25−30%)
production of C-3 ethyl ester (6a). The rate of the hydrolysis in
rat and monkey hepatocytes was not only slower but also the
formation of any products including C-3 ethyl ester (6a) was
minimal (<5%). The hydrolysis of the tebipenem pivoxyl (1) in
the liver microsomal preparations and hepatocytes from all the
species was rapid (<15 min) providing quantitative production
of tebipenem (2).
Carbapenems in general and ertapenem (3) in particular
have very low absorption due to high polar surface area, high
In order to test whether the poor absorption observed in rats
was species dependent, we studied the PK of compounds 4 and
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a
Table 3. Sprague-Dawley Rat (Fasted) Pharmacokinetics Measurement of Prodrugs by Intraduodenal (ID) Infusion Dosing
b
c
c
d
d
e
parameters
3 (IV, 1 mpk)
3 (ID, 10 mpk)
3 (PO, 10 mpk)
4 (ID, 10 mpk)
5 (ID, 10 mpk)
6 (ID, 4.4 mpk)
h
h
prodrug AUC(0−8) μM·h
3 AUC(0−8) μM·h
NA
7.84
NA
NA
NA
NA
0.48
NA
NA
0.39
NA
NQ
NQ
0.06
1.54
0.07
0.42
4.98
6.56
0.20
0.30
ND
ND
0.77
0.77
h
C-3 ester AUC(0−8) μM·h
benzoate ester AUC(0−8) μM·h
NQ
h
NA
NA
NQ
f
F% (3)
0.65
0.65
0.53
0.53
0.37
g
F% (Total)
NA
0.37
a
b
c
NA, not applicable; ND, not determined. Dosing vehicle (30% captisol, clear solution). Dosing vehicle (0.5% methyl cellulose [MC] clear
d
e
f
solution). Dosing vehicle (0.5% MC, homogeneous suspension). Dosing vehicle (0.5% MC, nearly clear solution). Calculated by dividing
normalized AUC of ertapenem formed from prodrug/normalized AUC of ertapenem dosed IV. Calculated by dividing normalized AUC of
circulating parent prodrug, ertapenem, and two monoesters formed from prodrug/normalized AUC of ertapenem dosed IV. Not quantifiable;
g
h
absolute data was below level of quantitation, 5 nM. The difference between AUC(0‑∞) vs AUC(0−8) was 20%.
a
Table 4. Beagle Dog (Fasted) Pharmacokinetics Measurement of Prodrugs by Intraduodenal (ID) Infusion Dosing
b
c
d
e
parameters
3 (IV,1 mpk)
4 (ID, 10 mpk)
6 (ID, 10 mpk)
7 (ID, 10 mpk)
h
prodrug AUC(0−8) μM·h
3 AUC(0−8) μM·h
NA
8.90
NA
NA
NA
NA
NQ
4.99
14.3
2.17
3.34
18.1
31.3
0.10
0.44
ND
1.81
0.04
C-3 ester AUC(0−8) μM·h
benzoate ester AUC(0−8) μM·h
h
NQ
ND
f
F% (3)
3.00
3.07
0.53
>0.65
g
F% (Total)
a
b
c
NA, not applicable; ND, not determined. Dosing vehicle (30% captisol, clear solution). Dosing vehicle (0.5% MC, homogeneous opaque
d
e
f
suspension). Dosing vehicle (10% Tween, nearly clear solution). Dosing vehicle (PEG400, hazy suspension). Calculated by dividing normalized
AUC of ertapenem formed from prodrug/normalized AUC of ertapenem dosed IV. Calculated by dividing normalized AUC of circulating parent
prodrug, ertapenem, and two monoesters formed from prodrug/normalized AUC of ertapenem dosed IV. Not quantifiable; absolute data was
g
h
below level of quantitation, 5 nM. The difference between AUC(0‑∞) vs AUC(0−8) was 20%.
6 in Beagle dogs by ID dosing. The absorption of compound 4
was only slightly improved in dogs showing 3% ertapenem in
plasma (Table 4). The results were significantly better for the
diethyl ester despite poor in vitro hydrolysis of the esters in the
dog plasma. Dosing of diethyl ester by ID route to dogs showed
about 18.1% absorption as measured in the form of ertapenem
and a total absorption of over 31.3% when the levels of both
monoesters (6a and 6b) and parent diethyl ester 6 and
ertapenem were combined (Table 4 and Figure 1). It is
Synthesis of ester prodrugs helped selection of compounds
with improved absorption of ertapenem leading to identi-
fication of the diethyl ester prodrug (6). It showed total
absorption of over 31%, which is in the range of a number of
clinically used cephalosporin prodrugs (e.g., ceftditoren pivoxil,
20%, cefcapene pivoxil, 27%).16,17 While the diethyl ester
prodrug established that noteworthy improvements in bioavail-
ability were achievable for this sensitive class of compounds,
robust clinical utility would require both greater absorption and
rapid liberation of the parent and will be the focus of future
efforts.
ASSOCIATED CONTENT
■
S
* Supporting Information
Graphical representation of time-dependent plasma hydrolysis
profile of 1 and 4−7, and syntheses and characterization of 4−
8. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Figure 1. Dog PK profile of diethyl ester (6).
Corresponding Author
*(S.B.S.) E-mail: sheo_singh@merck.com.
interesting to note that compound performed better in vivo
than in vitro conditions. More than 70% of the parent prodrug
was remaining after 60 min incubation in the in vitro hydrolysis
reaction in the dog plasma without producing any ertapenem.
The rate of the hydrolysis in liver microsomal preparations and
hepatocytes were also slower indicating that the hydrolysis in
vivo is far more efficient compared to in vitro. Encouraged by
this result, we tested the bis-lactone 7 for the dog PK by ID
dosing. It showed poor absorption, and only about 0.53%
ertapenem was present in the plasma. The intact prodrug (7)
was circulating in a ratio of 1:4 compared to ertapenem.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge technical assistance from Wuxi chemistry,
DMPK, and pharmaceutical sciences teams.
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REFERENCES
■
(1) Zhanel, G. G.; Wiebe, R.; Dilay, L.; Thomson, K.; Rubinstein, E.;
Hoban, D. J.; Noreddin, A. M.; Karlowsky, J. A. Comparative review of
the carbapenems. Drugs 2007, 67, 1027−1052.
(2) Kato, K.; Sekiguchi, T.; Kikuchi, A.; Iguchi, M.; Suzuki, H.;
Shibasaki, S.; Kurosawa, T.; Shirasaka, Y.; Tamai, I. Intestinal
absorption mechanism of tebipenem pivoxil, a novel oral carbapenem.
Drug Metab. Rev. 2007, 39, 74−75.
(3) Kobayashi, R.; Konomi, M.; Hasegawa, K.; Morozumi, M.;
Sunakawa, K.; Ubukata, K. In vitro activity of tebipenem, a new oral
carbapenem antibiotic, against penicillin-nonsusceptible Streptococcus
pneumoniae. Antimicrob. Agents Chemother. 2005, 49, 889−894.
(4) Sato, N.; Kijima, K.; Koresawa, T.; Mitomi, N.; Morita, J.; Suzuki,
H.; Hayashi, H.; Shibasaki, S.; Kurosawa, T.; Totsuka, K. Population
pharmacokinetics of tebipenem pivoxil (Me1211), a novel oral
carbapenem antibiotic, in pediatric patients with otolaryngological
infection or pneumonia. Drug Metab. Pharmacokinet. 2008, 23, 434−
446.
(5) Takahata, S.; Kato, Y.; Sanbongi, Y.; Maebashi, K.; Ida, T.
Comparison of the efficacies of oral beta-lactams in selection of
Haemophilus influenzae transformants with mutated Ftsi genes.
Antimicrob. Agents Chemother. 2008, 52, 1880−1883.
(6) Wang, Y.; Bolos, J.; Serradell, N. Tebipenem pivoxil/tebipenem.
Carbapenem antibiotic. Drugs Future 2006, 31, 676−681.
(7) Friedland, I.; Mixson, L. A.; Majumdar, A.; Motyl, M.; Woods, G.
L. In vitro activity of ertapenem against common clinical isolates in
relation to human pharmacokinetics. J. Chemother. 2002, 14, 483−491.
(8) Majumdar, A. K.; Musson, D. G.; Birk, K. L.; Kitchen, C. J.;
Holland, S.; McCrea, J.; Mistry, G.; Hesney, M.; Xi, L.; Li, S. X.;
Haesen, R.; Blum, R. A.; Lins, R. L.; Greenberg, H.; Waldman, S.;
Deutsch, P.; Rogers, J. D. Pharmacokinetics of ertapenem in healthy
young volunteers. Antimicrob. Agents Chemother. 2002, 46, 3506−3511.
(9) Stella, V. J. Prodrugs: Some thoughts and current issues. J. Pharm.
Sci. 2010, 99, 4755−4765.
(10) Stoeckel, K.; Tam, Y. K.; Kneer, J. Pharmacokinetics of oral
cefetamet pivoxil (RO-15-8075) and intravenous cefetamet (RO-15-
8074) in humans: a review. Curr. Med. Res. Opin. 1989, 11, 432−441.
(11) Chang, J. S.; El-Gamal, M. I.; Lee, W. S.; Anbar, H. S.; Chung,
H. J.; Kim, H. I.; Cho, Y. J.; Lee, B. S.; Lee, S. A.; Moon, J. Y.; Lee, D.
J.; Jeon, H. R.; Lee, J.; Choi, Y. W.; Oh, C. H. Design, synthesis,
bioconversion, and pharmacokinetics evaluation of new ester prodrugs
of olmesartan. Eur. J. Med. Chem. 2011, 46, 3564−3569.
(12) Anders, R.; Kleiman, J.; Nicholson, N.; Wazowicz, B.; Burns, D.
Xemilofiban/orbofiban: Insight into drug development. Cardiovasc.
Drug Rev. 2001, 19, 116−132.
(13) Krukemyer, J. J.; Talbert, R. L. Lovastatin: A new cholesterol-
lowering agent. Pharmacotherapy 1987, 7, 198−210.
(14) Li, B.; Sedlacek, M.; Manoharan, I.; Boopathy, R.; Duysen, E.
G.; Masson, P.; Lockridge, O. Butyrylcholinesterase, paraoxonase, and
albumin esterase, but not carboxylesterase, are present in human
plasma. Biochem. Pharmacol. 2005, 70, 1673−1684.
(15) Porter, A. E. The distribution of esterases in the animal body.
Biochem. J. 1916, 10, 523−533.
(16) Kato, K.; Shirasaka, Y.; Kuraoka, E.; Kikuchi, A.; Iguchi, M.;
Suzuki, H.; Shibasaki, S.; Kurosawa, T.; Tamai, I. Intestinal absorption
mechanism of tebipenem pivoxil, a novel oral carbapenem:
Involvement of human oatp family in apical membrane transport.
Mol. Pharmaceutics 2010, 7, 1747−1756.
(17) Matsumoto, F.; Sakurai, I.; Morita, M.; Takahashi, T.; Mori, N.;
Sugihara, T.; Sakai, A.; Yamaji, S.; Akaike, Y.; Yano, K. Effects of the
quantity of water and milk ingested concomitantly with AS-924, a
novel ester-type cephem antibiotic, on its pharmacokinetics. Int. J.
Antimicrob. Agents 2001, 18, 471−476.
719
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