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Vol. 291, Issue 3, 1068-1074, December 1999
Department of Drug Metabolism (W.T., R.A.S., G.Y.K., R.R.M., M.A.E., N.X.Y., D.C.D., S.K., T.A.B.) and Laboratory Animal Resources (S.A.I.), Merck Research Laboratories, Rahway, New Jersey; and Department of Drug Metabolism (M.S., J.H.L., T.A.B.), Merck Research Laboratories, West Point, Pennsylvania
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Abstract |
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 Top
 Abstract
 Introduction
Experimental Procedures
Results
Discussion
References
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The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is stimulated in vitro by quinidine. A similar effect is observed in incubations with monkey liver microsomes. We describe an in vivo interaction of diclofenac and quinidine that leads to enhanced clearance of diclofenac in monkeys. After a dose of diclofenac via portal vein infusion at 0.055 mg/kg/h, steady-state systemic plasma drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadministered with quinidine (0.25 mg/kg/h) via the same route, the corresponding plasma diclofenac concentrations were 50, 59, and 18 ng/ml, representing 57, 56, and 56% of control values, respectively. In contrast, steady-state systemic diclofenac concentrations in the same three monkeys were elevated 1.4 to 2.5 times when the monkeys were pretreated with L-754,394 (10 mg/kg i.v.), an inhibitor of CYP3A. Further investigation indicated that the plasma protein binding (>99%) and blood/plasma ratio (0.7) of diclofenac remained unchanged in the presence of quinidine. Therefore, the decreases in plasma concentrations of diclofenac after a combined dose of diclofenac and quinidine are taken to reflect increased hepatic clearance of the drug, presumably resulting from the stimulation of CYP3A-catalyzed oxidative metabolism. Consistent with this proposed mechanism, a 2-fold increase in the formation of 5-hydroxydiclofenac derivatives was observed in monkey hepatocyte suspensions containing diclofenac and quinidine. Stimulation of diclofenac metabolism by quinidine was diminished when monkey liver microsomes were pretreated with antibodies against CYP3A. Subsequent kinetic studies indicated that the Km value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus 59 µM), whereas Vmax increased 2.5-fold in the presence of quinidine. These data suggest that the catalytic capacity of monkey hepatic CYP3A toward diclofenac metabolism is enhanced by quinidine.
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Introduction |
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Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Cytochromes
P-450 (CYPs) are in many cases the primary enzymes involved in drug
metabolism (Wrighton and Stevens, 1992
; Guengerich, 1995). Changes in
CYP activities therefore have the potential to alter the
pharmacokinetic profile of a therapeutic agent and, in practice, lead
to a number of clinically important drug/drug interactions. For
example, if drugs A and B are coadministered and drug A is an inhibitor
of the CYP that is responsible for clearance of drug B, then the
systemic concentration of drug B could increase severalfold and exceed
its safety threshold (Lin and Lu, 1997). On the other hand, CYPs also
are known to be inducible; their expression may be elevated due to
transcriptional activation by xenobiotics or environmental factors
(Okey, 1990). Possible consequences of CYP induction include decreased
systemic exposure to a therapeutic agent or increased risks of forming
toxic metabolites (Conney, 1967). However, the effect of CYP induction
does not occur immediately after dosing of the inducer because the de
novo synthesis of CYP proteins takes place over a period of hours or days (Conney, 1967; Haugen et al., 1976).
In addition to mechanisms involving inhibition and induction, it is
known that CYP-mediated drug metabolism can be influenced (stimulated)
by the presence of certain xenobiotic compounds (activators; Guengerich, 1997). Such enhancement of CYP activity occurs
instantaneously and has been observed primarily in vitro in microsomal
incubations (Guengerich, 1997). Examples include the effect of
flavonoids on the oxidation of aflatoxin B1, benzo(a)pyrene,
and carbamazepine (Buening et al., 1981; Kerr et al., 1994). Similarly,
caffeine was shown to stimulate the bioactivation of acetaminophen in
incubations with rat liver microsomes (Lee et al., 1991). Corresponding
data derived from in vivo experiments, however, are rare. In one case, a flavone-dependent enhancement of zoxazolamine metabolism in rats was
reported, but the affected enzyme system was not characterized (Lasker
et al., 1982).
During our investigation of diclofenac bioactivation, it was observed
that the formation of CYP3A4-related metabolites increased more than
4-fold when incubations with human liver microsomes were performed in
the presence of quinidine (Fig. 1; Tang
et al., 1999b). Similar phenomena were observed with monkey
liver microsomes. These observations have led us to explore whether
this type of drug/drug interaction occurs in vivo. In this report, we
describe that the interaction of diclofenac and quinidine leads to
enhanced clearance of diclofenac in monkeys. The role of monkey hepatic CYP3A in the metabolism of diclofenac was investigated, and a correlation then was established between the hepatic clearance and the
metabolism of diclofenac in the presence of quinidine.
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Experimental Procedures |
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Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Materials. Diclofenac sodium salt, dimethyl sulfoxide, reduced glutathione (GSH), mefenamic acid, NADPH, quinidine, quinidine gluconate, and troleandomycin were purchased from Sigma Chemical Co. (St. Louis, MO). Trifluoroacetic acid (TFA) and polyethylene glycol 400 were obtained from Fisher Scientific (Fair Lawn, NJ). Ketoconazole was purchased from Janssen Biotech (Olen, Belgium). All other chemicals were obtained from Aldrich Chemical Co. (Milwaukee, WI). BondElut C18 solid-phase extraction cartridge columns were obtained from Varian Chromatography Systems (Walnut Creek, CA).
L-754,394 (N-[2-hydroxy-1-indanyl]-5-[2-[((1,1-dimethylethyl)amino) carbonyl]-4-[(furo[2,3-b]pyridin-5-yl)methyl]piperazin-1-yl]-4-hydroxy-2-(phenylmethyl)pentanamide) was synthesized at Merck Research Laboratories. [carbonyl-14C]Diclofenac (44.4 mCi/mmol, 99% radiochemical purity) was synthesized according to the published methodology (Horio et al., 1985). The synthesis of
4'-hydroxydiclofenac, 5-hydroxydiclofenac,
4'-hydroxy-3'-(glutathion-S-yl)diclofenac (4'-OH-3'-GS-diclofenac),
5-hydroxy-4-(glutathion-S-yl)diclofenac (5-OH-4-GS-diclofenac), and
5-hydroxy-6-(glutathion-S-yl)diclofenac (5-OH-6-GS-diclofenac) was reported previously (Tang et al., 1999a).
An antipeptide antibody against human hepatic CYP3A4 was prepared in
rabbits by immunization with a synthetic peptide that was identical
with residues 253 to 273 of CYP3A4 and was coupled to keyhole limpet
hemocyanin (Wang et al., 1997). A monoclonal antibody against human
hepatic CYP3A4 and monkey hepatic CYP3A was the product of hybridomas
derived from the fusion of myeloma cells and spleen cells from mice
immunized with baculovirus-expressed CYP3A4 (Mei et al., 1999).
Instrumentation and Analytical Methods. Liquid chromatography-tandem mass spectrometry (LC/MS/MS) was carried out on a Perkin-Elmer SCIEX API III+ tandem mass spectrometer (Toronto, Canada) interfaced to an HPLC system consisting of two Shimadzu LC-10A pumps and a static-bed mixer (Kyoto, Japan). LC/MS/MS experiments were performed using either an IonSpray interface or an atmospheric pressure chemical ionization interface with positive ion detection.
With the IonSpray interface, the ionization voltage was set at 5 kV, orifice potential at 65 V, collision energy at 30 eV, and collision gas (argon) at a thickness of 1.3 × 1014 atoms/cm2. Chromatography was performed on a DuPont Zorbax (Wilmington, DE) Rx-C8 column (4.6 × 250 mm, 5 µm), and samples were delivered at a flow rate of 1 ml/min with 1:25 split. The mobile phase consisted of aqueous acetonitrile containing 10% methanol and 0.05% TFA; a linear gradient was used in which the acetonitrile content increased from 10 to 70% during a 30-min period. With the atmospheric pressure chemical ionization interface, the heated nebulizer was set at 500°C, Corona discharge at 4.9 µA, orifice potential at 46 V, collision energy at 30 eV, and collision gas (argon) at a thickness of 2.0 × 1014 atoms/cm2. Chromatography was performed on a Keystone Scientific (Wilmington, DE) Betasil C8 column (4.6 × 50 mm, 5 µm), and samples were delivered at a flow rate of 1 ml/min. The mobile phase consisted of 90% aqueous acetonitrile containing 1 mM ammonium acetate and 0.1% TFA.Animal Experiments. Experiments were performed according to procedures approved by the Merck Research Laboratories Institutional Animal Care and Use Committee.
Three male rhesus monkeys (weight 5-6 kg) were treated with diclofenac (1 mg/kg) in an aqueous solution via i.v. injection. They were restrained in metabolism chairs for 6 h after dosing and then put into metabolism cages for the remainder of the study. Plasma was prepared from blood collected from peripheral veins at predosing and at various time points after dosing for 24 h. Three male rhesus monkeys (weight 8-10 kg) with catheters surgically implanted in their portal vein were treated with diclofenac (0.055 mg/kg/h) or a mixture of diclofenac (0.055 mg/kg/h) and quinidine (0.25 mg/kg/h) in aqueous solutions by portal infusion for 3.5 h. The monkeys were restrained in metabolism chairs during dosing and for 60 min after dosing. Plasma was prepared from blood collected from peripheral veins at before dosing and at various time points during and after the infusion. The three portal vein-cannulated monkeys were treated with L-754,394 (10 mg/kg) in ethanol/polyethylene glycol 400/water (10:40:50, v/v/v) by i.v. injection. After 10 min, they were dosed with diclofenac (0.055 mg/kg/h) in aqueous solutions via portal infusion for 3.5 h. The monkeys were restrained in metabolism chairs during dosing and for 60 min after dosing. Plasma was prepared from blood collected from peripheral veins before dosing and at various time points during and after the infusion. All monkeys had a 3-week washout period between treatments.Incubations with Monkey Hepatocytes.
Hepatocytes were
isolated from an adult male rhesus monkey through the use of a two-step
perfusion procedure (Pang et al., 1997). On isolation, hepatocytes that
exhibited a viability of greater than 80%, as determined with the
trypan blue exclusion test, were suspended in Krebs-bicarbonate buffer
(pH 7.4).
Incubations with Monkey Liver Microsomes.
Liver microsomes
were isolated by differential centrifugation (Raucy and Lasker, 1991)
and pooled from four male rhesus monkeys.
Detection and Quantification of Diclofenac and Its
Metabolites.
Aliquots of plasma (200 µl) were mixed with
mefenamic acid (internal standard, 20 ng) and 4 M urea (1 ml) and
applied to a 96-well plate solid-phase extraction cartridge that was
prewashed with methanol and water. The cartridge was washed
consecutively with water and 90% aqueous acetonitrile (400 µl)
containing 0.1% TFA. The acetonitrile eluate was analyzed by LC/MS/MS
(heated nebulizer interface) through multiple reaction monitoring of
mass transitions m/z 296
214 (diclofenac) and
m/z 242180 (internal standard). Standard curves were
generated over a range of 0.5 to 1000 ng.
542, 617488, 617342, and 617324 (Tang et
al., 1999b). Data are expressed relative to controls.
Determination of Blood/Plasma Ratio and Plasma Protein Binding of Diclofenac. Monkey blood (1 ml), preincubated at 37°C for 15 min, was treated with [14C]diclofenac in aqueous solution (pH 7.4) and quinidine in methanol. The final concentrations of diclofenac were 10, 50, 100, 150, and 200 ng/ml, all containing 0.0014 µCi of radiolabeled drug. The concentration of quinidine was 100 µM, and the methanol content was 0.2% (v/v). Controls contained no quinidine but the same amount of methanol (0.2%). All samples were incubated at 37°C for an additional 20 min. Plasma was then prepared, and radioactivity in the resulting samples (100 µl) was determined. Blood/plasma concentration ratios were estimated based on comparison of the radioactivity in plasma prepared from the treated blood samples with that in control plasma containing 0.0014 µCi of radiolabeled drug.
Monkey plasma (0.5 ml) in dialysis cells (Bel-Art Products, Pequannock, NJ) was spiked with [14C]diclofenac in aqueous solution (pH 7.4) and quinidine in methanol. The final concentrations of diclofenac were 10, 50, 100, and 200 ng/ml, all containing 0.0014 µCi of radiolabeled drug. The concentration of quinidine was 100 µM, and that of methanol was 0.2% (v/v). Controls contained no quinidine but the same amount of methanol (0.2%). The dialysis membrane (Sigma Chemical Co., St. Louis, MO) had a molecular mass cutoff of 12.4 kDa. The resulting plasma samples then were subjected to dialysis against isotonic phosphate buffer for 3 h. The protein-bound fraction was determined through a comparison of the differences between radioactivity in the plasma and that in the buffer solution.Pharmacokinetic Calculations. Pharmacokinetic parameters of diclofenac in monkeys were calculated based on a noncompartment model. Values for the plasma clearance and volume of distribution are presented as means ± S.D.
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Results |
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Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Pharmacokinetics of Diclofenac in Monkeys. The pharmacokinetic parameters of diclofenac were determined in three male rhesus monkeys after i.v. dosing at 1 mg/kg. The plasma clearance was 8.7 ± 0.7 ml/min/kg, and the volume of distribution, extrapolated to steady state, was 0.17 ± 0.04 l/kg. The terminal phase half-life was estimated at 0.51 ± 0.17 h.
Studies on the interaction of diclofenac and quinidine were carried out in three male rhesus monkeys with catheters surgically implanted in their portal vein. The experiment was designed such that two monkeys were treated with diclofenac, and the third received diclofenac plus quinidine. Three weeks later, the same monkeys were treated with diclofenac or diclofenac plus quinidine in a crossover manner. Systemic plasma diclofenac concentrations reached steady-state at approximately 105 min (~3 times the terminal half-life) after the start of the portal vein infusion (0.055 mg/kg/h); these steady-state concentrations were measured as the mean values of six time-points during 120 to 195 min of infusion. Thus, after a dose of diclofenac (control), plasma drug concentrations at steady-state in the three monkeys were 87, 104, and 32 ng/ml, respectively. When diclofenac was coadministered (0.055 mg/kg/h) with quinidine (0.25 mg/kg/h) via portal vein infusion, the corresponding plasma diclofenac concentrations were 50, 59, and 18 ng/ml, which represent 56% of the control values (Fig. 2).
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). After portal vein infusion
of diclofenac at 0.055 mg/kg/h, plasma drug concentrations at steady
state were 136, 141, and 82 ng/ml, respectively, a 1.4- to 2.5-fold
increase compared with control values (Fig. 2). The more profound
effect on plasma diclofenac concentrations observed in the third monkey
after L-754,394 dosing probably is associated with a relatively higher
metabolic capacity in that monkey. Because L-754,394 is a
mechanism-based inhibitor of CYP3A, more rapid turnover of the
inhibitor would result in less active enzyme.
Metabolism of Diclofenac in Monkey Hepatocytes and Liver
Microsomes.
The detection of diclofenac metabolites in hepatocyte
suspensions or in incubations with liver microsomes was based on LC/MS multiple reaction monitoring coupled with HPLC separation (Tang et al.,
1999a). Because the monohydroxylated metabolites of diclofenac in these
in vitro systems have been shown to undergo further biotransformation to form reactive intermediates (Tang et al., 1999a,b), diclofenac metabolism in this study was evaluated by monitoring the formation of
the GSH adducts of hydroxydiclofenac. Thus, when 50 µM diclofenac was
incubated with monkey hepatocytes, two 5-hydroxydiclofenac derivatives,
namely 5-OH-4-GS-diclofenac and 5-OH-6-GS-diclofenac, were the major
metabolites, whereas their 4'-hydroxy analog, 4'-OH-3'-GS-diclofenac, was a minor product (Fig. 3). Compared
with controls, a 2-fold increase in the formation of
5-hydroxydiclofenac derivatives was observed in suspensions containing
quinidine.
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), the apparent Km determined by
monitoring the formation of 5-OH-4-GS-diclofenac and
5-OH-6-GS-diclofenac actually may reflect the
Km of a single-step reaction from
diclofenac to 5-hydroxydiclofenac.
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Inhibition of CYP-Mediated Metabolism of Diclofenac.
Diclofenac metabolism in incubations with monkey liver microsomes was
inhibited by CYP3A inhibitors, namely troleandomycin, ketoconazole, and
L-754,394 (Table 1). The inhibition also
was observed when microsomes were treated with antibodies against CYP3A
(Table 1). With the monoclonal antibodies, nearly complete inhibition
was achieved. The concentrations of the inhibitors and the antibodies
against CYP3A were selected based on literature values generated with
human liver microsomes (Newton et al., 1995; Mei et al., 1999; Tang et
al., 1999b).
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Blood/Plasma Ratio and Plasma Protein Bindings of Diclofenac. The blood-to-plasma concentration ratio of diclofenac in monkeys was determined in vitro over a concentration range of 10 to 200 ng/ml. The ratio was estimated at 0.7. When quinidine was coadministered at the final concentration of 100 µM, the blood/plasma concentration ratio of diclofenac remained unchanged.
The plasma protein binding of diclofenac in monkeys was investigated in vitro over a drug concentration range of 10 to 200 ng/ml. The binding was estimated to be greater than 99%. In the presence of 100 µM quinidine, the plasma protein binding of diclofenac remained greater than 99%.| |
Discussion |
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Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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The oxidative metabolism of diclofenac in humans mainly involves
CYP2C9 and 3A4 (Fig. 1; Leemann et al., 1993; Shen et al., 1999; Tang
et al., 1999b). The CYP3A4-catalyzed formation of 5-hydroxydiclofenac in incubations with human liver microsomes was reported to be stimulated by the presence of quinidine (Tang et al., 1999b). To
investigate whether the observed effect of quinidine on diclofenac metabolism also occurs in vivo, our initial efforts focused on choosing
an appropriate animal model.
The clearance of diclofenac is known to be due largely to metabolism,
but the mechanism of clearance differs considerably among species in
terms of partition between phase I and phase II pathways. For example,
glucuronidation and taurine conjugation contribute nearly 90% to the
elimination of diclofenac in dogs, whereas CYP-catalyzed hydroxylation
is the primary route of clearance in rats and monkeys (Riess et al.,
1978; Stierlin and Faigle, 1979). The stimulatory effect of quinidine,
however, was not observed in incubations of diclofenac with rat liver
microsomes (data not shown). This is probably due to the participation
in rats of several CYP enzymes (CYP2B, 2C and 3A subfamilies) in
diclofenac metabolism where CYP3A is not a predominant contributor
(Tang et al., 1999a).
On the other hand, high CYP3A activities are observed in monkey liver
(Sharer et al., 1995). In our study with CYP inhibitors and inhibitory
antibodies, monkey hepatic CYP3A was demonstrated to catalyze the
conversion of diclofenac to 5-hydroxydiclofenac derivatives that were
the major metabolites in rhesus monkeys dosed with the drug (Riess et
al., 1978; Stierlin and Faigle, 1979). More importantly, the formation
of 5-hydroxy derivatives increased 3-fold when incubations of
diclofenac with monkey liver microsomes were performed in the presence
of quinidine. This phenomenon is similar to that observed in
incubations with human liver microsomes (Tang et al., 1999b).
Consequently, the effect of quinidine on diclofenac metabolism was
investigated in vivo in the rhesus monkey.
In rhesus monkeys, diclofenac appeared to be a low clearance compound
with blood clearance estimated at 12 ml/min/kg, approximately one
fourth of hepatic blood flow in this species (44 ml/min/kg; Davies and
Morris, 1993). This estimate was made based on two parameters
determined in this study: the plasma clearance of 8.7 ml/min/kg and the
blood-to-plasma ratio of 0.7. The systemic plasma diclofenac
concentration reached steady state after portal vein infusion for 105 min. This route of administration provides the advantages of maximizing
the first-pass effect and controlling exposure quantitatively.
Subsequent in vivo studies of the effect of quinidine consisted of two
experiments. In the first, monkeys were administered diclofenac
together with quinidine via portal vein infusion. Coadministration of
quinidine was associated with lower steady-state plasma diclofenac concentrations that occurred in a time frame too short for the de novo
synthesis of CYP proteins (Conney, 1967, Haugen et al., 1976). In the
second experiment, monkeys were treated with L-754,394, an inhibitor of
CYP3A, followed by a dose of diclofenac via portal vein infusion. In
this study, steady-state plasma diclofenac concentrations increased
1.4- to 2.5-fold relative to controls. Further investigation indicated
that neither diclofenac plasma protein binding nor blood/plasma ratio
was influenced by the presence of quinidine. Taken together, these data
suggest that the hepatic clearance of diclofenac, measured on the basis
of the portal infusion rate and steady-state plasma drug
concentrations, is increased on quinidine coadministration. This
increase in the clearance of diclofenac most likely results from the
stimulation of oxidative metabolism catalyzed by CYP3A. Consistent with
this proposed mechanism, a 2-fold increase in the formation of
5-hydroxydiclofenac derivatives was observed in monkey hepatocyte
suspensions containing diclofenac and quinidine. Moreover, the
stimulative effect of quinidine on diclofenac metabolism was diminished
when monkey liver microsomes were pretreated with antibodies against
CYP3A. Therefore, it may be concluded that the stimulation is mediated
through the interaction of quinidine with CYP3A.
Quinidine is an antiarrhythmic drug (Grace and Camm, 1998). In a
research setting, however, quinidine has been used extensively as an
inhibitor of CYP2D6 (Newton et al., 1995; Bourrie et al., 1996).
Several reports indicate that quinidine also is an inhibitor of CYP3A4,
albeit a weak one (Schellens et al., 1991; Bowles et al., 1993). The
inhibitory effect on CYP3A4 presumably is competitive in nature because
quinidine metabolism is catalyzed by that enzyme (Guengerich et al.,
1986). In contrast, our studies suggest that CYP3A-mediated metabolism
of diclofenac is enhanced by quinidine. In the presence of quinidine,
the Km value for monkey hepatic CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was
little changed, whereas the Vmax increased
2.5-fold. It is tempting to speculate, therefore, that quinidine is a
modulator of CYP3A activity and that its effect may be either
inhibitory or stimulatory depending on the nature of the CYP3A
substrate. Studies are under way to investigate this hypothesis.
In summary, the CYP3A-dependent oxidative metabolism of diclofenac is stimulated by quinidine. In monkeys, quinidine coadministration leads to increased hepatic clearance of diclofenac. This case appears to be a rare example in which stimulation of CYP-mediated xenobiotic metabolism is observed in vivo. Whether a similar drug-drug interaction occurs in humans remains to be established.
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Acknowledgments |
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We thank our colleagues at Merck Research Laboratories, namely, Jianmei Peng for isolation of monkey hepatocytes; Regina Wang for preparation of the anti-peptide antibody; Bonnie Friscino, Alison Kulick, Allison Parlapiano, Lisa Stanislawczyk, and Jayne Wilcox for assistance in animal experiments; and Dr. Shuet-Hing Chiu and Judy Fenyk-Melody for suggestions. We also thank Dr. Anthony Lu at Rutgers University for valuable discussions.
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Footnotes |
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Accepted for publication August 18, 1999.
Received for publication June 7, 1999.
Send reprint requests to: Wei Tang, Ph.D., Department of Drug Metabolism, Merck & Co., P.O. Box 2000, RY80L-109, Rahway, NJ 07065. E-mail: wei_tang{at}merck.com
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Abbreviations |
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CYP, cytochrome P-450; GSH, reduced glutathione; LC/MS/MS, liquid chromatography/tandem mass spectrometry; 4'-OH-3'-GS-diclofenac, 4'-hydroxy-3'-(glutathion-S-yl)diclofenac; 5-OH-4-GS-diclofenac, 5-hydroxy-4-(glutathion-S-yl)diclofenac; 5-OH-6-GS-diclofenac, 5-hydroxy-6-(glutathion-S-yl)diclofenac; TFA, trifluoroacetic acid.
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References |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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-naphthoflavone or phenobarbital.
J Biol Chem
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A. Galetin, S. E. Clarke, and J. B. Houston MULTISITE KINETIC ANALYSIS OF INTERACTIONS BETWEEN PROTOTYPICAL CYP3A4 SUBGROUP SUBSTRATES: MIDAZOLAM, TESTOSTERONE, AND NIFEDIPINE Drug Metab. Dispos., September 1, 2003; 31(9): 1108 - 1116. [Abstract] [Full Text] [PDF]
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T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al. THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVE Drug Metab. Dispos., July 1, 2003; 31(7): 815 - 832. [Abstract] [Full Text] [PDF]
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A.-C. Egnell, B. Houston, and S. Boyer In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1251 - 1262. [Abstract] [Full Text] [PDF]
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 T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al. The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A PhRMA Perspective J. Clin. Pharmacol., May 1, 2003; 43(5): 443 - 469. [Abstract] [Full Text] [PDF]
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S. Kumar, G. Y. Kwei, G. K. Poon, S. A. Iliff, Y. Wang, Q. Chen, R. B. Franklin, V. Didolkar, R. W. Wang, M. Yamazaki, et al. Pharmacokinetics and Interactions of a Novel Antagonist of Chemokine Receptor 5 (CCR5) with Ritonavir in Rats and Monkeys: Role of CYP3A and P-Glycoprotein J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1161 - 1171. [Abstract] [Full Text] [PDF]
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A. Galetin, S. E. Clarke, and J. B. Houston Quinidine and Haloperidol as Modifiers of CYP3A4 Activity: Multisite Kinetic Model Approach Drug Metab. Dispos., December 1, 2002; 30(12): 1512 - 1522. [Abstract] [Full Text] [PDF]
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Y. Masubuchi, A. Ose, and T. Horie Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine Drug Metab. Dispos., October 1, 2002; 30(10): 1143 - 1148. [Abstract] [Full Text] [PDF]
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J. A. Williams, B. J. Ring, V. E. Cantrell, D. R. Jones, J. Eckstein, K. Ruterbories, M. A. Hamman, S. D. Hall, and S. A. Wrighton Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7 Drug Metab. Dispos., August 1, 2002; 30(8): 883 - 891. [Abstract] [Full Text] [PDF]
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J. M. Hutzler and T. S. Tracy Atypical Kinetic Profiles in Drug Metabolism Reactions Drug Metab. Dispos., April 1, 2002; 30(4): 355 - 362. [Full Text] [PDF]
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K. E. Kenworthy, S. E. Clarke, J. Andrews, and J. B. Houston Multisite Kinetic Models for CYP3A4: Simultaneous Activation and Inhibition of Diazepam and Testosterone Metabolism Drug Metab. Dispos., December 1, 2001; 29(12): 1644 - 1651. [Abstract] [Full Text] [PDF]
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R. E. White and P. Manitpisitkul Pharmacokinetic Theory of Cassette Dosing in Drug Discovery Screening Drug Metab. Dispos., July 1, 2001; 29(7): 957 - 966. [Abstract] [Full Text] [PDF]
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J. S. Ngui, Q. Chen, M. Shou, R. W. Wang, R. A. Stearns, T. A. Baillie, and W. Tang In Vitro Stimulation of Warfarin Metabolism by Quinidine: Increases in the Formation of 4'- and 10-Hydroxywarfarin Drug Metab. Dispos., June 1, 2001; 29(6): 877 - 886. [Abstract] [Full Text]
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J. S. Ngui, W. Tang, R. A. Stearns, M. Shou, R. R. Miller, Y. Zhang, J. H. Lin, and T. A. Baillie Cytochrome P450 3A4-Mediated Interaction of Diclofenac and Quinidine Drug Metab. Dispos., September 1, 2000; 28(9): 1043 - 1050. [Abstract] [Full Text]
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