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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 7, Number 7, October 2006
Contents
In Vivo Animal Models
for Investigating Potential CYP3A- and Pgp-Mediated Drug-Drug
Interactions Pp. 687-704
P.H. Marathe and A.D. Rodrigues
[Abstract]
The Functional Role of CYP2B6 in Human Drug Metabolism:
Substrates and Inhibitors In Vitro, In Vivo
and In Silico Pp. 705-714
M. Turpeinen, H. Raunio and O. Pelkonen
[Abstract]
Bioactivation and Hepatotoxicity of Nitroaromatic
Drugs Pp. 715-727
U.A. Boelsterli, H.K. Ho, S. Zhou and K. Y. Leow
[Abstract]
The Potential of Flavonoids to Influence Drug
Metabolism and Pharmacokinetics by Local Gastrointestinal
Mechanisms Pp. 729-744
R. Cermak and S. Wolffram
[Abstract]
Inhibition of Human Phenol and Estrogen Sulfotransferase
by Certain Non-Steroidal Anti-Inflammatory Agents Pp.
745-753
R.S. King, A.A. Ghosh and J. Wu
[Abstract]
Metabolism of Green Tea Catechins: An Overview
Pp. 755-809
W.Y. Feng
[Abstract]
Oral L-Carnitine: Metabolite Formation and Hemodialysis
Pp. 811-816
M.A. Bain, R. Faull, R.W. Milne and A.M. Evans
[Abstract]
Loading-Washout Studies of the Stereoselective
Sinusoidal Uptake of (R)- and (S)-2-Phenylpropionyl
Acyl Glucuronide Pp. 817-826
D.M. Shackleford, A.M. Evans, R.W. Milne and R.L. Nation
[Abstract]
Clinical Utility of a Pharmacostatistical Model
for Ibandronate in Postmenopausal Osteoporosis Pp.
827-836
J.-Y. Reginster and R. Gieschke
[Abstract]
Abstracts
[Back to top]
In Vivo Animal Models for
Investigating Potential CYP3A- and Pgp-Mediated Drug-Drug
Interactions
P.H. Marathe and A.D. Rodrigues
With the advent of polytherapy it has become prudent to minimize,
as much as possible, the potential for drug-drug interactions.
Towards this end, the metabolic and transporter pathways involved
in the disposition of a drug candidate (phenotyping) are evaluated
in vitro employing available human tissue and specific
reagents. Likewise, in vitro screening for inhibition
and induction of drug-metabolizing enzymes and transporters
is conducted also. Such in vitro human data can be
made available prior to human dosing and enable in vitro
to in vivo-based predictions of clinical outcomes.
Despite some success, however, in vitro systems are
not dynamic and sometimes fail to predict drug-drug interactions
for a variety of reasons. In comparison, relatively less effort
has been made to evaluate predictions based on data derived
from in vivo animal models. This review will attempt
to summarize different examples from the literature where
animal models have been used to predict cytochrome P450 3A
(CYP3A)- and P-glycoprotein (Pgp)-based drug-drug interactions.
When employing data from animal models one needs to be aware
of species differences in pharmacokinetics, clearance pathways
and selectivity and affinity of probe substrates and inhibitors.
Because of these differences, in vivo animal studies
alone, cannot be predictive of human drug-drug interactions.
Despite these caveats, the information obtained from validated
in vivo animal models may prove useful when used
in conjunction with in vitro-in vivo extrapolation
methods. Such an integrated data set can be used to select
drug candidates with a reduced drug interaction potential.
[Back to top]
The Functional Role of CYP2B6 in Human Drug Metabolism:
Substrates and Inhibitors In Vitro, In Vivo
and In Silico
M. Turpeinen, H. Raunio and O. Pelkonen
CYP2B6 metabolizes a number of drug substrates, that are usually
non-planar, neutral or weakly basic, fairly lipophilic with
one or two hydrogen bond acceptors, on which it catalyses
various oxidative reactions. For bupropion, cyclophosphamide,
ifosfamide, pethidine, ketamine and propofol, these reactions
represent major metabolic or activation pathways and for their
kinetics CYP2B6 function is of considerable importance. For
the rest of the substrates found, CYP2B6 contributes to overall
metabolism or to a single pathway, but probably not to a materially
significant extent. Among inhibitors, thiotepa, ticlopidine
and clopidogrel have been characterised extensively in terms
of selectivity and potency. Thiotepa is the most selective
of the inhibitors, but is not useful as an in vivo
inhibitor, whereas ticlopidine and clopidogrel can be used
as CYP2B6-selective probes in human clinical studies. Bupropion
hydroxylation is a selective, and consequently useful, in
vivo probe for CYP2B6. Computational approaches are being
developed to the extent that predictions on affinity of chemicals
to CYP2B6 are becoming reliable enough as a first screen of
new drug molecules and other chemicals. With validated in
vitro and in vivo substrates (e.g. bupropion)
and inhibitors (e.g. ticlopidine), it is expected that pharmacological
(including pharmacogenetic) and clinical significance of CYP2B6
will be delineated more fully in the near future.
[Back to top]
Bioactivation and Hepatotoxicity of Nitroaromatic
Drugs
U.A. Boelsterli, H.K. Ho, S. Zhou and K. Y. Leow
Certain drugs containing a nitroaromatic moiety (e.g., tolcapone,
nimesulide, nilutamide, flutamide, nitrofurantoin) have been
associated with organ-selective toxicity including rare cases
of idiosyncratic liver injury. What they have in common is
the potential for multistep nitroreductive bioactivation (6-electron
transfer) that produces the potentially hazardous nitroanion
radical, nitroso intermediate, and N-hydroxy derivative.
These intermediates have been associated with increased oxidant
stress and targeting of nucleophilic residues on proteins
and nucleic acids. However, other mechanisms including the
formation of oxidative metabolites and mitochondrial liability,
as well as inherent toxicokinetic properties, also determine
the drugs’ overall potency. Therefore, structural modification
not only of the nitro moiety but also of ring substituents
can greatly reduce toxicity. Novel concepts have revealed
that, besides the classical microsomal nitrore-ductases, cytosolic
and mitochondrial enzymes including nitric oxide synthase
can also bioactivate certain nitroarenes (nilutamide). Furthermore,
animal models of silent mitochondrial dysfunction have demonstrated
that a mitochondrial oxidant stress posed by certain nitroaromatic
drugs (nimesulide) can produce significant mitochondrial injury
if superimposed on a genetic mitochondrial abnormality. Finally,
there may be mechanisms for all nitroaromatic drugs that do
not involve bioactivation of the nitro group, e.g., AHR interactions
with flutamide. Taken together, the focus of research on the
hepatic toxicity of nitroarene-containing drugs has shifted
over the past years from the identification of the reactive
intermediates generated during the bioreductive pathway to
the underlying biomechanisms of liver injury. Most likely
one of the next paradigm shifts will include the identification
of determinants of susceptibility to nitroaromatic drug-induced
hepatotoxicity.
[Back to top]
The Potential of Flavonoids to Influence Drug Metabolism
and Pharmacokinetics by Local Gastrointestinal Mechanisms
R. Cermak and S. Wolffram
In recent years, public and scientific interest in plant flavonoids
has tremendously increased due to postulated health benefits.
Whereas the amount of flavonoids ingested with the regular
diet is rather low, the use of supplements enriched with these
polyphenolics is becoming increasingly popular. This raises
concerns about possible interactions of flavonoids with therapeutic
drugs, because both are xenobiotics and, thus, share at least
partially the same metabolic pathways. A number of in
vitro studies have shown effects of flavonoids on enzymes
involved in xenobiotic metabolism, like cytochrome P450 monooxygenases
and phase II conjugation enzymes, or on membrane transporters
involved in drug excretion. Several investigations have also
reported changes of drug bioavailability by certain flavonoids.
This article attempts to present an overview of flavonoid
effects on pathways involved in drug metabolism. It focuses
on phase I and phase II enzymes as well as on transporters
involved in drug metabolism which are expressed in the gastrointestinal
tract.
[Back to top]
Inhibition of Human Phenol and Estrogen Sulfotransferase
by Certain Non-Steroidal Anti-Inflammatory Agents
R.S. King, A.A. Ghosh and J. Wu
We hypothesized that aryl acetate- and aryl carboxylate-containing
drugs would inhibit human phenol sulfotransferase (SULT1A1),
and that selectivity would depend upon the interaction of
the aryl portion of the molecule with the sulfotransferase
acceptor binding site. This hypothesis was based on results
with the rat orthologue showing that oxidation of phenolic
substrates to carboxylate derivatives resulted in competitive
inhibition of rat phenol sulfotransferase. We chose nine structurally
representative non-steroidal anti-inflammatory agents and
determined their inhibitory potency and selectivity toward
SULT1A1 and expressed human estrogen sulfotransferase (SULT1E1).
The results show that the tested agents reversibly inhibit
SULT1A1 activity with IC50 ranging from 0.1 μM
to 3800 μM.
These agents also inhibited SULT1E1 (IC50 = 6 μM
to 9000 μM).
The agents were clearly isoform selective, with IC50
ratios (1E1/1A1) ranging from 0.01 to 200. Nimesulide, meclofenamate,
and piroxicam were more selective towards SULT1A1 inhibition,
while sulindac and ibuprofen were more selective towards SULT1E1
inhibition. Sulfotransferase inhibition was maintained after
substituting the carboxylate with enolate (nimesulide) or
methylsulfonamide (piroxicam). Kinetic studies determined
the type of inhibition of SULT1A1 for three agents (meclofenamate,
nimesulide, aspirin) to be non-competitive or partial non-competitive
versus both substrate (p-nitrophenol) and cofactor
(PAPS). This inhibition mechanism indicates that meclofenamate,
nimesulide and aspirin bind near enough to the substrate binding
site to prevent catalysis but not affect dissociation of the
substrate-enzyme complex. The inhibition of SULT1A1 by meclofenamate,
nimesulide, salicylate and aspirin may be clinically relevant
based on ratio of inhibition constant to predicted in
vivo inhibitor concentration ([I]/IC50>1).
[Back to top]
Metabolism of Green Tea Catechins: An Overview
W.Y. Feng
Green tea is one of the most popular beverages worldwide.
Its major components include (-)-epicatechin ((-)-EC), (-)-epicatechin-3-gallate
(ECG) (-)-epigallocatechin (EGC) and (-)-epigallocatechin-3-gallate
(EGCG). It has demonstrated strong antioxidative, anti-inflammatory
and anti-cancerous properties and attracted a great deal of
interest over last several years. However, there is some discrepancy
between the results from human pidemiological studies and
cultured cell and animal models. Two reasons for its limited
in vivo activities have been considered: metabolism
and bioavailability. Recent studies have demonstrated that
green tea catechins undergo methylation, glucuronidation and
sulfation in in vitro systems and in animals and
in humans. It has been also found that efflux transporters
Pgp, MRP1 and MRP2 play roles in the absorption and excretion
of green tea catechins. Several processes including intestinal
metabolism, microbial metabolism, hepatic metabolism and chemical
degradation have been found to be involved in the fate of
green tea, and to be responsible for its low availability
in animals, and most likely also in humans. Pharmacokinetics,
absorption, distribution, drug metabolism and excretion properties
of green tea provide a better understanding for its in
vivo activities. In this article, drug metabolism and
microbial metabolism of green tea catechins in in vitro
systems and in animals and in humans will be reviewed. It
also covers the factors affecting their biotransformation
and bioavailability: drug-drug inhibitory and inductive interactions
of phase I and phase II enzymes, inhibition of non-drug-metabolizing
enzymes, transporters, chemical instability, epimerization
and interindividual variability.
[Back to top]
Oral L-Carnitine: Metabolite Formation and Hemodialysis
M.A. Bain, R. Faull, R.W. Milne and A.M. Evans
L-Carnitine has important roles in intermediary metabolism
and patients with end-stage renal disease who are undergoing
hemodialysis may develop a secondary L-carnitine deficiency.
The extent of accumulation of the metabolites trimethylamine
and trimethylamine-N-oxide when L-carnitine is administered
orally has not been investigated previously in this population.
Oral L-carnitine at a dose of 1 g daily was administered for
twelve days to six patients with end-stage renal disease undergoing
hemodialysis thrice weekly. Pre-dialysis plasma concentrations
of L-carnitine (mean ± SD) increased significantly
(P < 0.05) from day 1 (baseline; 32.4 ±
6.1 µM) to day 8 (66.1 ± 13.8 µM) remaining
constant thereafter. Although plasma levels of trimethylamine
remained unaltered, the pre-dialysis plasma concentrations
of trimethylamine-N-oxide increased significantly
(P < 0.05) from day 1 (289.1 ± 236.1 µM)
to day 12 (529.0 ± 237.9 µM). The hemodialysis
clearances for L-carnitine, trimethylamine and trimethylamine-N-oxide
were 14.3 ± 8.2, 14.1 ± 10.6 and 12.4 ±
5.4 L/h, respectively, indicating their efficient removal
by dialysis. Oral administration of L-carnitine at a dose
of 1 g daily increases plasma concentrations of this substance
to physiological levels in patients with end-stage renal disease
who are undergoing hemodialysis. However, concerns about the
possible deleterious consequences of such a dosage regimen
still remain given that plasma concentrations of trimethylamine-N-oxide
were continually rising and approximately doubled in a two-week
period.
[Back to top]
Loading-Washout Studies of the Stereoselective Sinusoidal
Uptake of (R)- and (S)-2-Phenylpropionyl
Acyl Glucuronide
D.M. Shackleford, A.M. Evans, R.W. Milne and R.L. Nation
The vectorial movement of glucuronide conjugates from blood
into bile can be an important elimination route for many drug
metabolites, however the intrinsic hydrophilicity of those
conjugates may conceptually act to reduce the overall efficiency
of that process by limiting the flux of such conjugates across
the sinusoidal membrane domain of hepatocytes. In this investigation,
the hepatic disposition of the diastereomeric glucuronides
of (R)- and (S)-2-phenylpropionic acid (a model "profen"
compound) have been studied using the isolated perfused rat
liver to establish whether a permeability barrier at the sinusoidal
membrane domain (demonstrated previously for those conjugates)
is of a sufficient magnitude to impact on the overall biliary
excretion of these conjugates.
Livers were perfused (30 mL/min) with perfusate containing
either (R)-PPA, (S)-PPA, (R)-PPA-Glucuronide or (S)-PPA-Glucuronide
in order to determine the dispositional profile of each glucuronide
administered to the liver as both a preformed and an hepatically-generated
metabolite. Once an apparent steady-state condition had been
reached, infusion of test compound was ceased in order to
establish the kinetics of the hepatic washout.
The extent of biliary excretion of each glucuronide was dependent
upon whether the glucuronide was presented to the liver as
a preformed or hepatically-generated metabolite, and those
differences, when analysed using a physiologically-based pharmacokinetic
model, were consistent with the sinusoidal membrane acting
as a barrier to the cellular entry of the glucuronides. Furthermore,
that barrier was more pronounced for (R)-PPAG than it was
for (S)-PPAG, suggesting that the hepatocellular uptake of
the two diastereomers is stereoselective.
[Back to top]
Clinical Utility of a Pharmacostatistical Model for
Ibandronate in Postmenopausal Osteoporosis
J.-Y. Reginster and R. Gieschke
Ibandronate, a potent, nitrogen-containing bisphosphonate
for the treatment of postmenopausal osteoporosis, is the subject
of an ongoing clinical development program to explore novel
oral and intravenous (i.v.) dosing regimens. As part of this
program, an extensive modeling and simulation project was
undertaken to develop and validate a pharmacologically realistic
mathematical model for ibandronate in osteoporosis, the aim
being to identify practical dosing regimens for clinical evaluation.
A simplified kinetics of drug action or kinetic-pharmacodynamic
(K-PD) model (developed from a 4-compartment pharmacokinetic-pharmacodynamic
[PK-PD] model) accurately described the urinary excretion
of the C-telopeptide of the α-chain
of type I collagen (uCTX). The model was extended to consider
the effects of supplemental calcium therapy and allow simultaneous
fitting of i.v. and oral ibandronate data, and then externally
validated. This model was used successfully in the selection
of appropriate once-monthly doses for further clinical evaluation
and recent clinical studies have confirmed the efficacy of
the doses identified. Further development of the model may
include investigating the effects of ibandronate on bone mineral
density and fracture risk, which would further enhance its
clinical utility and predictive value. Although modeling and
simulation has been used to explore the efficacy of other
bisphosphonates, the extensive program with ibandronate has
produced a comprehensively validated model that is the first
to be prospectively tested by evaluating novel dosing regimens.
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