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Dear all,
Do any of you have knowledge of the clinical importance on CYP2C8?=20
Any drugs meing metabolised via this isozyme?
Kind regards,
Thomas Senderovitz, MD
Associate Head of Clinical Pharmacology
=46erring Pharmaceuticals A/S - International Center
Clinical Research/Clinical Pharmacology
Borups All=E9 177
DK-2400 Copenhagen NV
Denmark
Direct phone: +45 38 15 04 58
Direct Fax: +45 38 15 03 05
Mobile phone: +45 24 25 52 24
E-mail: thomas.senderovitz.-a-.ferring.com
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[Hot topic - quite a few replies - db]
Date: Tue, 28 Mar 2000 00:45:07 -0700 (MST)
X-Sender: ml11439.-at-.pop.goodnet.com
To: PharmPK.aaa.boomer.org
From: ml11439.-a-.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK CYP2C8
Dr.Senderovitz,
CYP2C9 is the isoenzyme primarily responsible for the metabolism
of S-warfarin. Other CYP2C isoenzymes listed in Goodman& Gillman's are
CYP2C10, CYP2C18 and CYP2C19.
Mike Leibold, PharmD, RPh
ML11439.at.goodnet.com
---
Date: Tue, 28 Mar 2000 02:52:44 -0700 (MST)
X-Sender: ml11439.at.pop.goodnet.com
To: PharmPK.aaa.boomer.org
From: ml11439.at.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK CYP2C8
Dr.Senderovitz,
The cytochrome P450 (CYP) system refers to a group of liver isoenzymes
located in the endoplasmic reticulum of the hepatocytes that are responsible
for the oxidative metabolism of numerous endogenous and exogenous compounds.
The designation P450 is derived from the heme-containing enzyme absorbance
of light at 450 nanometers in their reduced form. At least 30 related
isoenzymes have been identified, and 11 have been confirmed as potential
sites of drug metabolism. The nomenclature for these enzymes is based on
assignment to a
family, a subfamily, and a gene product. For example, CYP 2D6 represents
that this cytochrome is a member of family number 2, subfamily D, and gene
product 6. Other major CYP isoforms involved in drug metabolism are 3A4,
2C9, 1A2, and 2E1.
It is estimated that CYP 3A is responsible for the oxidative metabolism
of over 50% of drugs and hormones, more than any other CYP subfamily.
CYP2C9 is the isoenzyme primarily responsible for the metabolism
of S-warfarin. Other CYP2C isoenzymes (or gene products)listed in Goodman&
Gilman's are CYP2C10, CYP2C18 and CYP2C19.
Mike Leibold, PharmD, RPh
ML11439.at.goodnet.com
---
From: "Shoaf, Susan"
To: "'PharmPK.-a-.boomer.org'"
Subject: RE: PharmPK CYP2C8
Date: Tue, 28 Mar 2000 08:13:16 -0500
For extensive enzyme metabolism information see Dr. S. Rendic's P450
database maintained by Gentest.
You must register to enter.
http://www.gentest.com/human_p450_database/index.html
Susan Shoaf
Susan E. Shoaf, Ph.D.
Clinical Pharmacokineticist
Otsuka America Pharmaceutical, Inc.
---
X-OpenMail-Hops: 1
Date: Tue, 28 Mar 2000 09:16:44 -0500
Subject: Re: PharmPK CYP2C8
From: Tong_William/mskcc_MOL.aaa.mskmail.mskcc.org
TO: PharmPK.at.boomer.org
Taxol
Bill Tong
Memorial Sloan Kettering Cancer Center
---
Date: Tue, 28 Mar 2000 09:14:20 -0600
To: PharmPK.-at-.boomer.org
From: "Thomas N. Kakuda, Pharm.D."
Subject: Re: PharmPK CYP2C8
According to Rendic S and Di Carlo FJ (Drug Metab Reviews 1997; 29: 413-580),
the following drugs are substrates for CYP2C8:
Antipyrine
Carbamazepine
Clozapine
Cyclophosphamide
(S) and (R) Ibuprofen
Ifosfamide
Omeprazole
Paclitaxel
Phenytoin
Sulfadiazine
Temazepam
Tolbutamide
Trimethoprim
(R) Warfarin
Zidovudine
Rifampin and phenytoin induce CYP2C8 and barbiturates, sulfaphenazole,
and sulfinpyrazone inhibit. Hope this helps.
Sincerely,
Thomas N. Kakuda, Pharm. D.
University of Minnesota
7-152 Weaver-Densford Hall
308 Harvard Street SE
Minneapolis, MN 55455
(612) 624-9156
(612) 625-9931 (FAX)
---
Date: Tue, 28 Mar 2000 10:31:51 -0500 (EST)
From: kvenkata.at.OPAL.TUFTS.EDU
Subject: 2C8
To: PharmPK.-at-.boomer.org
CYP2C8 is the major isoform that metabolizes taxol in humans. It also
participates in one of the pathways of retinoic acid metabolism. The
clinical relevance of this isoform to human drug metabolism is still not
completely established for other drugs.
---
X-Sender: desaipb.aaa.email.uc.edu
Date: Tue, 28 Mar 2000 14:38:42 -0500
To: PharmPK.at.boomer.org
From: Pankaj Desai
Subject: Re: PharmPK CYP2C8
Anti-cancer agent paclitaxel is the best known substrate for this enzyme.
I believe rosiglitazone is metabolized by CYP2C8.
Dr. Pankaj Desai
Associate Professor Biopharmaceutics and Pharmacokinetics
College of Pharmacy
University of Cincinnati Medical Center
3223 Eden Avenue
Cincinnati, OH 45267-0004
---
X-Originating-IP: [203.197.255.53]
From: "NVSRAO MAMIDI"
To: PharmPK.-at-.boomer.org
Subject: Re: PharmPK CYP2C8
Date: Tue, 28 Mar 2000 19:26:16 PST
Dear Dr. Thomas:
Taxol (Taxol 6-hydroxylation)and Carbamezepine are metabolized by
CYP2C8. To best of my knowledge no inducer known to induce this
isozyme. Quercitin is known to inhibit the cyp2c8 mediated
metabolism. I am not very aware of drug-drug interactions which are
due to this isozyme.
regards.
N.V.S.Rao Mamidi Ph.D
Senior Scientist
Drug Metabolisma and Pharmacokinetics
Dr. reddy's Research Foundation
Hyderabad- 500 016
India
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[Thanks and more replies - db]
From: Thomas.Senderovitz.-at-.ferring.com
To: PharmPK.aaa.boomer.org
Subject: RE: PharmPK Re: CYP2C8
Date: Wed, 29 Mar 2000 08:55:17 +0200
Dear all,
Thanks for the extensive answering of my question. Many of the
answers were quite useful, although it seems that the clinical
significance of CYP2A8 is still not completely known. At least it is
not included in all internet CYP-sites.
Best regards,
Thomas Senderovitz, MD
Associate Head of Clinical Pharmacology
Ferring Pharmaceuticals A/S - International Center
Clinical Research/Clinical Pharmacology
Borups All=E9 177
DK-2400 Copenhagen NV
Denmark
Direct phone: +45 38 15 04 58
Direct Fax: +45 38 15 03 05
Mobile phone: +45 24 25 52 24
E-mail: thomas.senderovitz.-a-.ferring.com
---
Date: Wed, 29 Mar 2000 00:50:32 -0700 (MST)
X-Sender: ml11439.aaa.pop.goodnet.com
To: PharmPK.-at-.boomer.org
From: ml11439.aaa.goodnet.com (Michael J. Leibold)
Subject: Re: CYP2C8
Dr.Senderovitz,
Evidently Goodman& Gilman's must be in error regarding the CYP2c family
of isoenzymes, since CYP2C8 was not included in their list. Further research
indicates that there are four human CYP2Cs (2C8,2C9, 2C18, and 2C19).(2)
As per the following references, CYP2C8 is involved in the metabolism
of paclitaxel, all-transretinoic acid, zopiclone, and troglitazone (recently
withdrawn from the market due to hepatotoxicity). (1-4)
Mike Leibold, PharmD, RPh
ML11439.at.goodnet.com
<1>
Unique Identifier
20123347
Authors
Yamazaki H. Suzuki M. Tane K. Shimada N. Nakajima M. Yokoi T.
Institution
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa
University, Japan. yanazak.at.kenroku.kamazawa-u.ac.jp
Title
In vitro inhibitory effects of troglitazone and its metabolites on drug
oxidation activities of human cytochrome P450 enzymes: comparison with
pioglitazone and rosiglitazone.
Source
Xenobiotica. 30(1):61-70, 2000 Jan.
Abstract
1. Investigated were the effects of a new oral antidiabetic drug,
troglitazone, and its three metabolites and antidiabetic drug candidates
pioglitazone and rosiglitazone on xenobiotic oxidations catalyzed by nine
recombinant human cytochrome P450 (P450 or CYP) enzymes and by human liver
microsomes. 2. Troglitazone (5 microM) significantly inhibited
CYP2C8-dependent paclitaxel 6alpha-hydroxylation and
CYP2C9-dependent S-warfarin 7-hydroxylation. On the other hand, pioglitazone
and rosiglitazone (50 microM) only slightly inhibited these xenobiotic
oxidation activities catalyzed by CYP2C enzymes. 3. The inhibitory potential
of troglitazone (50% inhibition concentration, IC50) was approximately 5
microM for drug oxidations catalyzed by CYP2C9 and CYP2C8
and approximately 20 microM for activities catalyzed by CYP2C19 and CYP3A4
respectively. For the three metabolites of troglitazone tested, a
quinone-type metabolite (M3) was the most potent inhibitor for CYP2C enzymes,
followed by a sulphate conjugate (M1); effects of a glucuronide (M2) were
very weak. The inhibitory effects of the parent drug were more potent than
those of metabolites. Troglitazone and M3 inhibited P450 activities mainly
through a competitive manner with Ki =3D 0.2-1.7 microM and 1.4-8.8 microM
respectively. 4. In three human liver microsomes, troglitazone and its
metabolites also inhibited paclitaxel 6alpha-hydroxylation, S-warfarin
7-hydroxylation, S-mephenytoin 4'-hydroxylation, and testosterone
6beta-hydroxylation with similar IC50, as observed for the recombinant P450
enzyme systems. 5. These results suggest that xenobiotic oxidations by P450
enzymes are more substantially affected by troglitazone and its metabolites
than pioglitazone or rosiglitazone, and that drug interactions may be of much
importance to understand the basis for the pharmacological and toxicological
actions of this new oral antidiabetic drug.
<2>
Unique Identifier
99415356
Authors
Klose TS. Blaisdell JA. Goldstein JA.
Institution
Laboratory of Pharmacology and Chemistry, National Institute of Environmental
Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Title
Gene structure of CYP2C8 and extrahepatic distribution of
the human CYP2Cs.
Source
Journal of Biochemical & Molecular Toxicology. 13(6):289-95, 1999.
Abstract
Extrahepatic tissue distribution of the mRNAs for the four human CYP2Cs (2C8,
2C9, 2C18, and 2C19) was examined in kidney, testes, adrenal gland, prostate,
brain, uterus, mammary gland, ovary, lung, and duodenum. CYP2C mRNAs were
detected by RT-PCR using specific primers for each individual CYP2C.
CYP2C8 mRNA was detected in the kidney, adrenal gland,
brain, uterus, mammary gland, ovary, and duodenum. CYP2C9 mRNA was detected
in the kidney, testes, adrenal gland, prostate, ovary, and duodenum. CYP2C18
mRNA was found only in the brain, uterus, mammary gland, kidney, and duodenum
and CYP2C19 mRNA was found only in the duodenum. Immunoblot analysis of small
intestinal microsomes detected both 2C9 and 2C19 proteins. In addition,
genomic clones for CYP2C8 were sequenced, and long-distance
PCR was performed to determine the complete gene structure.
CYP2C8 spanned a 31 kb region. Comparative analysis of the
2.4 kb upstream region of CYP2C8 with CYP2C9 revealed two
previously unidentified transcription factors sites, C/EBP and HPF-1, and the
latter might be involved in hepatic expression. Although
CYP2C8 has been shown to be phenobarbital inducible, neither
a barbiturate-responsive regulatory sequence (a Barbie box) nor a
phenobarbital-responsive enhancer module (PBREM) was found within the
upstream region analyzed.
<3>
Unique Identifier
99391718
Authors
Becquemont L. Mouajjah S. Escaffre O. Beaune P. Funck-Brentano C.
Jaillon P.
Institution
Clinical Pharmacology Unit, Saint Antoine University Hospital, School of
Medicine Paris 6, France. becquemo.-at-.b3e.jussieu.fr
Title
Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism.
Source
Drug Metabolism & Disposition. 27(9):1068-73, 1999 Sep.
Abstract
Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is
extensively metabolized by the liver in humans. The aim of the present study
was to identify the human cytochrome P-450 (CYP) isoforms involved in
zopiclone metabolism in vitro. Zopiclone metabolism was studied with
different human liver microsomes and a panel of heterologously expressed
human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver
microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and
N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84
+/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z
generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited
approximately 40% of the generation of both metabolites, sulfaphenazole
(CYP2C inhibitor) inhibited the formation of ND-Z, whereas
alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1)
did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were
highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r =3D
0.95 and 0.92, respectively; p =3D.0001), and ND-Z was highly correlated to
CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r =3D 0.76, p
=3D.004). Recombinant CYP2C8 had the highest enzymatic
activity toward zopiclone metabolism into both its metabolites, followed by
CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism
in vitro, and CYP2C8 contributes significantly to ND-Z
formation.
<4>
Unique Identifier
99411879
Authors
Nadin L. Murray M.
Institution
Department of Medicine, University of Sydney, Westmead Hospital, NSW,
Australia.
Title
Participation of CYP2C8 in retinoic acid 4-hydroxylation in
human hepatic microsomes.
Source
Biochemical Pharmacology. 58(7):1201-8, 1999 Oct 1.
Abstract
Cytochromes P450 (CYPs) catalyze the 4-hydroxylation of all-trans-retinoic
acid (ATRA), an agent used in the treatment of certain malignancies.
Literature studies have implicated several CYPs in this reaction, but the
relative importance of individual CYPs is unclear. Human microsomal CYPs that
contribute to the activity were evaluated by correlation with activities of
hepatic drug-metabolizing CYPs, the capacity of cDNA-derived CYPs to catalyze
the reaction, and inhibition of the microsomal activity by chemicals.
4-HydroxyATRA formation in microsomes varied 7-fold (8.7 to 61 pmol/mg
protein/min) and correlated partially with activities mediated by CYPs 3A,
2C, and 1A (p =3D 0.53 to 0.66). cDNA-derived CYPs 2C8, 2C9, and 3A4, but not
1A1 or 1A2, catalyzed ATRA 4-hydroxylation (2.53, 4.68, and 1.29 pmol/pmol
CYP/hr). The Km for the reaction was 9 +/- 3 microM in hepatic microsomes (N
=3D 3) and 6 microM in microsomes containing cDNA-derived
CYP2C8; by comparison, Km values for the activity mediated
by CYPs 2C9 and 3A4 were 100 and 74 microM, respectively. Inhibition of
microsomal ATRA 4-hydroxylation was elicited by chemicals that interact with
CYP2C8 (paclitaxel and diclofenac), but not those that
interact with CYP2C9 (sulfaphenazole, tolbutamide, and torasemide). The CYP3A
inhibitor troleandomycin and an anti-CYP3A IgG inhibited the activity
slightly. Greater inhibition was produced by the less selective CYP3A
inhibitors parathion, quinidine, and ketoconazole; CYP1A inhibitors were
ineffective. These findings suggest that CYP2C8 is a major
contributor to ATRA 4-hydroxylation in human liver and that 3A subfamily CYPs
may be minor participants. Individual variation in CYP2C8
and 3A4 expression may influence ATRA pharmacokinetics and drug interactions
during therapy.
---
X-Sender: prema.-a-.192.168.1.1
Date: Wed, 29 Mar 2000 08:34:45 -0500
To: PharmPK.at.boomer.org
From: Chandrani Gunaratna
Subject: Re: PharmPK CYP2C8
Dear Dr. Senderovitz,
One of the drugs mainly metabolized by CYP2C8 is taxol (taxol
6-hydroxylation). Another drug is carbamazepine. Quercetin is an inhibitor
for this isozyme.
Hope this helps.
Chandrani Gunaratna
Chandrani Gunaratna, Ph.D.
Senior Research Scientist
Bioanalytical Systems
2701 Kent Avenue
West Lafayette, IN 47906
Phone: (765)463-4527
E-Mail: prema.at.bioanalytical.com
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