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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 8, Number 2, February 2007
Contents
Ocular Disposition, Pharmacokinetics, Efficacy
and Safety of Nanoparticle-Formulated Ophthalmic Drugs
Pp. 91-107
H.-Z. Bu, H.J. Gukasyan, L. Goulet, X.-J. Lou, C. Xiang
and T. Koudriakova
[Abstract]
Pharmacokinetic and Pharmacodynamic Variability: A
Daunting Challenge in Drug Therapy Pp. 109-136
J.H. Lin
[Abstract]
Identification of a Novel Intestinal First Pass Metabolic
Pathway: NQO1 Mediated Quinone Reduction and Subsequent Glucuronidation
Pp. 137-149
H. Hao, G. Wang, N. Cui, J. Li, L. Xie and Z. Ding
[Abstract]
Diffusion of Macromolecule Through Retina After Experimental
Branch Retinal Vein Occlusion and Estimate of Intraretinal
Barrier Pp. 151-156
Y. Tao, X.-x. Li, Y.-r. Jiang, X.-b. Bai, B.-d. Wu and
J.-q. Dong
[Abstract]
A Mechanistic Study on Altered Pharmacokinetics of
Irinotecan by St. John’s Wort Pp. 157-171
Z.-P. Hu, X.-X. Yang, X. Chen, J. Cao, E. Chan, W. Duan,
M. Huang, X-Q. Yu, J.-Y. Wen and S.-F. Zhou
[Abstract]
Metabolism of Sanguinarine: The Facts and The Myths
Pp. 173-176
Z. Dvorák and V. Šimánek
[Abstract]
Modulation of Neurotransmitter Release by Carbon Monoxide
at the Frog Neuro-Muscular Junction Pp. 177-184
G.F. Sitdikova, R.R. Islamov, M.A. Mukhamedyarov, V.V.
Permyakova, A.L. Zefirov and A. Palotás
[Abstract]
Transcriptional Regulation and Expression of CYP3A4
in Hepatocytes Pp. 185-194
C.P. Martínez-Jiménez, R. Jover, M.T. Donato,
J.V. Castell and M.J. Gómez-Lechón
[Abstract]
Abstracts
[Back to top]
Ocular Disposition, Pharmacokinetics, Efficacy
and Safety of Nanoparticle-Formulated Ophthalmic Drugs
H.-Z. Bu, H.J. Gukasyan, L. Goulet, X.-J. Lou, C. Xiang
and T. Koudriakova
Ophthalmic drugs are delivered to ocular tissues predominantly
via relatively simple formulations, such as topically dosed
water-soluble drug solutions and water-insoluble drug suspensions
in ointments. An ideal topical drug delivery system should
possess certain desirable properties, such as good corneal
and conjunctival penetration, prolonged precorneal residence
time, easy instillation, non-irritative and comfortable to
minimize lachrymation and reflex blinking, and appropriate
rheological properties. In general, ocular efficacy is closely
related to ocular drug bioavailability, which may be enhanced
by increasing corneal drug penetration and prolonging precorneal
drug residence time. To improve ocular bioavailability of
topically dosed ophthalmic drugs, a variety of ocular drug
delivery systems, such as hydrogels, microparticles, nanoparticles,
microemulsions, liposomes and collagen shields, have been
designed and investigated. These newer systems may, to some
extent, control drug release and maintain therapeutic levels
in ocular tissues over a prolonged period of time. This review
focuses on the in vitro, ex vivo and in
vivo studies of ophthalmic drugs formulated in nanoparticles
published over the past two decades. The progress and development
issues relating to ocular disposition, pharmacokinetics, efficacy
and safety of the nanoparticle-formulated ophthalmic drugs
are specifically addressed. Information and discussions summarized
in this review are helpful for pharmaceutical scientists to
develop better ophthalmic therapeutics.
[Back to top]
Pharmacokinetic and Pharmacodynamic Variability: A
Daunting Challenge in Drug Therapy
J.H. Lin
Patients vary considerably in their response to drug therapy.
A drug that proves to be pharmacologically effective in some
patients at a given dose may be ineffective or even toxic
in others. The interindividual variability in drug response
represents a major challenge in drug therapy, particularly
for drugs with narrow therapeutic index. The intensity and
duration of a drug action are determined not only by pharmacokinetic
processes, but also by pharmacodynamic processes. Therefore,
the variability in drug response is a result of the variability
in either pharmacokinetic or pharmacodynamic processes, or
a combination of both. The purpose of this paper is to review
the sources that contribute to pharmacokinetic and pharmacodynamic
variability. Although the main focus will be on the genetic
variability, the impact of environmental factors on drug response
will also be discussed. Finally, the application and limitation
of the concept of personalized medicine will be briefly discussed.
[Back to top]
Identification of a Novel Intestinal First Pass Metabolic
Pathway: NQO1 Mediated Quinone Reduction and Subsequent Glucuronidation
H. Hao, G. Wang, N. Cui, J. Li, L. Xie and Z. Ding
Quinones represent a very important class of compounds found
in nature and for the chemically synthesized drugs. The present
study was designed to elucidate the intestinal first pass
metabolic pathways in vivo and in vitro,
of tanshinone IIA (TS), a derivative of phenanthrene-quinone
isolated from Salvia miltiorrhiza. Five metabolites,
proposed to be TS catechol glucuronides (two position isomers),
dehydrotanshinone IIA and its two catechol glucuronides, were
identified from the rat intestinal homogenates after oral
administration of TS. TS metabolism was further conducted
in the subcellular system including cytosol, microsomes, mitochondrial
and S9 under both phase I and phase II metabolic conditions.
TS underwent negligible metabolism in all of the subcellular
systems under phase I metabolic condition using NADPH as the
cofactor. However, significant and substantial metabolic elimination
of TS was observed in the cytosol and S9 fractions, while
not in the microsomes fractions, when both NADPH and UDPGA
were added. Two TS catechol glucuronides were identified from
such an in vitro metabolic medium. Dicoumarol, a
specific inhibitor of the NAD(P)H dependent quinone oxidoreductase
(NQO1), significantly inhibited the metabolic elimination
of TS in a noncompetitive way, suggesting that NQO1 was responsible
for the quinone reduction of TS to form the catechol intermediate.
The catechol intermediate failed to be detected directly was
proved to be highly unstable and autoxidized back to TS accompanied
with hydrogen peroxide generation. Dicoumarol exhibited a
significant inhibitory effect on the hydrogen peroxide generation,
further supporting that the reduction of TS was catalyzed
by NQO1. The absolute bioavailability of TS was significantly
enhanced by oral dicoumarol pretreatment. In conclusion, a
novel intestinal metabolic pathway for quinones, NQO1 mediated
reduction and subsequent glucuronidation, was determined using
TS as a model compound. This study should be helpful for the
general understanding of quinones absorption and intestinal
first pass metabolism.
[Back to top]
Diffusion of Macromolecule Through Retina After Experimental
Branch Retinal Vein Occlusion and Estimate of Intraretinal
Barrier
Y. Tao, X.-x. Li, Y.-r. Jiang, X.-b. Bai, B.-d. Wu and
J.-q. Dong
The disposition and diffusion knowledge of intravitreally
injected macromolecule drugs through retina in pathological
condition is crucial but the related studies are absent. Retinal
edema is a common pathological change of fundus diseases and
retinal vein occlusion (RVO) pig model were established to
emulate it. FITC-dextrans of various molecular weights were
dissolved in RPMI-1640 solutions and the rate of transretinal
diffusion was determined with a spectrophotometer. Theoretical
maximum size of molecule (MSM) was calculated by extrapolating
the trend-linear relationship with the diffusion rate. In
separate experiments to determine the sites of barrier to
diffusion, FITC-dextrans were applied to either the inner
or outer retinal surface, processed as frozen sections, and
viewed with a fluorescence microscope. Paired-Samples T test
was used to compared the diffusion rate of dextrans of the
both eyes of one pig. The MSM in RVO tissues and normal tissue
was 6.5+0.39nm and 6.18+0.54nm respectively (t=4.143, P=0.0001).
FITC-dextrans applying to inner retinal surface, 4.4 kDa dextran
were largely arrested at inner nuclear layer (INL). The INL
of the 19.6~71.2 kDa dextran diffusion retina section became
dark and the nerve fiber layer (NFL) and inner plexiform layer
got brighter. As for 150 kDa dextran, the NFL was bright and
the other layers were dark. FITC-dextrans applying to outer
retinal surface, most dextrans were blocked before outer nuclear
layer (ONL). In summary, ONL and INL may act as bottle-neck
barriers to diffusion of macromolecules. Compared with normal
neuroretina, the MSM of fresh edema retina after RVO increased
limitedly.
[Back to top]
A Mechanistic Study on Altered Pharmacokinetics of
Irinotecan by St. John’s Wort
Z.-P. Hu, X.-X. Yang, X. Chen, J. Cao, E. Chan, W. Duan,
M. Huang, X-Q. Yu, J.-Y. Wen and S.-F. Zhou
Irinotecan (CPT-11) is an important anticancer drug in management
of advanced colon cancer. A marked protective effect on CPT-11-induced
blood and gastrointestinal toxicity is obtained by combination
of St. John’s wort (SJW) in recent clinical and rat
studies. However, the mechanism is unclear. This study aimed
to explore the effects of SJW on the pharmacokinetics of CPT-11
and its major metabolites (SN-38 and SN-38 glucuronide) in
rats and the underlying mechanisms using several in vitro
models. Short-term (3 days) and long-term (14 days) pretreatment
with SJW were conducted in rats to examine the effects of
co-administered SJW on the plasma pharmacokinetics of CPT-11,
SN-38 and SN-38 glucuronide. Rat liver microsomes and a rat
hepatoma cell line, H4-II-E cells, were utilized to study
the effects of aqueous and ethanolic extracts (AE and EE)
and major active components (hyperforin, hypericin and quercetin)
of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation.
Co-administered SJW for consecutive 14 days significantly
decreased the initial plasma concentration (C0)
of CPT-11, the area under the concentration-time curve (AUC0-10hr)
and maximum plasma concentration (Cmax) of SN-38.
The ethanolic extracts (EE) of SJW at 5 μg/ml
significantly decreased SN-38 glucuronidation by 45% (P
< 0.05) in rat hepatic microsomes. Pre-incubation of aqueous
SJW extracts (AE) at 10 μg/ml,
SJW EE at 5 μg/ml,
and quercetin at 10 μM
significantly increased the glucuronidation of SN-38 in H4-II-E
cells. A 2-hr pre-incubation of quercetin (100 µM) significantly
increased the intracellular accumulation of CPT-11 (P
< 0.05). However, pre-incubation of hypericin (20 nM and
200 nM) and hyperforin (1µM) significantly decreased
the intracellular accumulation of CPT-11. In addition, pre-incubation
of hypericin, SJW EE and quercetin significantly increased
the intracellular accumulation of SN-38. Aqueous and ethanolic
SJW extracts and its major active components did not alter
the plasma protein binding of CPT-11 and SN-38. These results
indicated that the aqueous and ethanolic extracts of SJW and
its major active components could markedly alter glucuronidation
of SN-38 and intracellular accumulation of CPT-11 and SN-38,
which probably provides partial explanation for the altered
plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing
effects on the toxicities of CPT-11. Further studies are needed
to explore the role of both pharmacokinetic and pharmacodynamic
components in the protective effect of SJW against the toxicities
of CPT-11.
[Back to top]
Metabolism of Sanguinarine: The Facts and The Myths
Z. Dvorák and V. Šimánek
Sanguinarine, a quaternary benzo[c]phenanthridine alkaloid,
exhibits antimicrobial and anti-inflammatory activities and
for this reason it is used in dental hygiene products and
feed additives. Its metabolism and disposition is the subject
of constant scientific discourse. In this paper we summarize
current knowledge on sanguinarine metabolism. We show in particular
that: (i) Sanguinarine is not transformed to 3,4-benzacridine
and that the literature reporting this compound as a metabolite
of sanguinarine is based on artifacts and misinterpretations
that in course of time have created a dogma; (ii) Sanguinarine
is converted to dihydrosanguinarine in vivo, the
conversion being tentatively a detoxication pathway; (iii)
Aryl hydrocarbon receptor metabolic signaling pathways modulate
sanguinarine biological activity.
[Back to top]
Modulation of Neurotransmitter Release by Carbon Monoxide
at the Frog Neuro-Muscular Junction
G.F. Sitdikova, R.R. Islamov, M.A. Mukhamedyarov, V.V.
Permyakova, A.L. Zefirov and A. Palotás
Carbon monoxide (CO) is an endogenous gaseous messenger, which
regulates numerous physiological functions in a wide variety
of tissues. Using extracellular microelectrode recording from
frog neuro-muscular preparation the mechanisms of exogenous
and endogenous CO action on evoked quantal acetyl-choline
(Ach) release were studied. It was shown that CO application
increases Ach-release in dose-dependent manner without changes
in pre-synaptic Na+ and K+ currents.
The effect of exogenous CO on Ach-release was decreased by
prior application of guanylate cyclase inhibitor ODQ and prevented
by application of a cyclic guanylate monophospate (cGMP) analog
8Br-cGMP. Pre-treatment of the preparation with adenylate
cyclase inhibitor MDL-12330A has completely abolished the
effect of CO, whereas elevation of intracellular level of
cyclic adenosine monophospate (cAMP) mimicked and eliminated
CO action. Application of cGMP-activated phosphodiestherase-2
inhibitor EHNA did not prevent CO action, whereas inhibition
of cGMP-inhibited phosphodiestherase-3 by quazinone has partially
blocked the effect of CO. Utilizing immuno-histochemical methods
CO-producing enzyme heme-oxygenase-2 (HO-2) was shown to be
expressed in skeletal muscle fibers, mostly in sub-sarcolemmal
region, karyolemma and sarcoplasmic reticulum. Zn-protoporphirin-IX,
the selective HO-2 blocker, has depressed Ach-release, suggesting
the tonic activating effect of endogenous CO on pre-synaptic
function. These results suggest that facilitatory effect of
CO on Ach-release is mediated by elevation of intracellular
cAMP level due to activation of adenylate cyclase and decrease
of cAMP breakdown. As such, endogenous skeletal muscle-derived
CO mediates tonic ret-rograde up-regulation of neuro-transmitter
release at the frog neuro-muscular junction.
[Back to top]
Transcriptional Regulation and Expression of CYP3A4
in Hepatocytes
C.P. Martínez-Jiménez, R. Jover, M.T. Donato,
J.V. Castell and M.J. Gómez-Lechón
CYP3A4 is the most abundantly expressed drug-metabolizing
P450 enzyme in human liver and contributes to the metabolism
of a large number of drugs in use today. CYP3A4 is constitutively
expressed in adult hepatocytes but it can also be transcriptionally
induced by a variety of structurally diverse xenochemicals.
CYP3A4 strongly contributes to the important variability in
the therapeutic and toxic effects of drugs owing to the major
role it plays in xenobiotic metabolism and the large intra-
and inter-individual variability to which it is subjected.
The functional examination of up to 13 kb of the CYP3A4
5'-flanking region has revealed that the regulation of this
gene is a complex issue, with numerous transcription factors
interacting with multiple promoter/enhancer elements. This
also suggests that a high degree of human variability in the
hepatic CYP3A4 expression could result from regulatory polymorphisms.
Several transcription factors and nuclear receptors contribute
to the hepatic-specific expression of CYP3A4, including: C/EBPα,
C/EBPβ,
HNF4α,
HNF3γ,
CAR and PXR. The induction phenomenon and the down-regulation
of CYP3A4 in pathophysiological conditions, such as inflammatory
situations, are key processes involved in the toxic vs.
therapeutic effects of many drugs. Since CYP3A4 variation
may affect the efficacy and toxicity of new drugs, development
of reliable hepatic models for the assessment and prediction
of the role of CYP3A4 in drug metabolism are important for
drug development. Cultured human hepatocytes are the closest
model to the human liver as far as CYP3A4 regulation
and induction are concerned. However, other hepatic models
should be considered in drug development for screening purposes
owing to the limited availability of human hepatocytes.
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