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Hello dear all,
I was wondering if there is a, like debrisoquine for 2D6, to be used in man.
Erik F.O. Pomp
DI-pharmacist
Bergen, Norway
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[Sorry all, I managed make a mess of the original message sent by Erik. In
my attempt to create a useful subject for the message I moved the phrase
'reference test substrate (or commonly used) for CYP2C9' from the message
instead of copying it - sorry about the confusion - actually a good
collection of responses for both enzyme systems - db]
ORIGINAL MESSAGE!
Hello dear all,
I was wondering if there is a reference test substrate (or commonly used)
for CYP2C9, like debrisoquine for 2D6, to be used in man.
Kind regards
Erik F.O. Pomp
DI-pharmacist
Bergen, Norway
---
[ A few replies to the orginal post - db]
CYP2C9 replies:-
X-Originating-IP: [132.203.39.201]
From: Ashish Sharma
To: PharmPK.-at-.boomer.org
Subject: Re: PharmPK Reference test substrate for CYP2C9
Date: Tue, 22 Jun 1999 22:39:35 PDT
Mime-Version: 1.0
Hello Erik:
As such some of the substrates for CYP2C9 are: Losartan, warfarin,
cerivastatin and fluvastatin. However, when you say to be used in man, if
you mean for phenotyping, tolbutamide might be an interesting candidate I
suppose.
Hope that is helpful.
=C2shish Sharma
PhD student
Facult=E9 de Pharmacie
Universit=E9 Laval,
Qu=E9bec, Canada
---
From: Per Damkier
To: "'PharmPK.at.boomer.org'"
Subject: RE: PharmPK Reference test substrate for CYP2C9
Date: Wed, 23 Jun 1999 09:15:17 +0200
MIME-Version: 1.0
Hi Erik
The best documentated in vivo biomarker reaction for CYP2C9 is the
tolbutamide metabolic ratio. For a reference see:
Veronese EV et al.: "Validation of the tolbutamide..." Clin Pharmacol Ther
1990;47:403-411.
Regards
Per Damkier
Denmark
---
From: "Alex Hemeryck"
To: PharmPK.at.boomer.org
Date: Wed, 23 Jun 1999 09:25:20 +0200
MIME-Version: 1.0
Subject: Re: PharmPK Reference test substrate for CYP2C9
Priority: normal
Hello dear readers,
Yes, there is: tolbutamide (4-methylhydroxylation) is widely
accepted as a prototypic substrate for the assessment of hepatic
CYP2C9 activity, both in vitro and in vivo.
For further information, I would like to refer you to the recently
published (review) article of
Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major
importance in human drug metabolism. Br J Clin Pharmacol
1998;45:525-538
Sincerely,
A. Hemeryck
****************************************
Alex Hemeryck
Pharmacist
Heymans Institute of Pharmacology
University of Ghent
Medical School
De Pintelaan 185
B-9000 Gent
Tel: +32-9-2403370
Fax: +32-9-2404988
e-mail: Alex.Hemeryck.aaa.rug.ac.be
****************************************
---
X-Lotus-FromDomain: WATSON
From: nsingh.-at-.watsonpharm.com
To: PharmPK.-a-.boomer.org
Cc: Multiple recipients of PharmPK - Sent by
Date: Wed, 23 Jun 1999 06:52:59 -0700
Subject: Re: PharmPK Reference test substrate for CYP2C9
MIME-Version: 1.0
Phenytoin (widely studied), tolbutamide and many of the NSAIDs are good prob=
es
for CYP2C9.
=3D=3D=3D
2D6 replies:-
From: "Aziz"
To:,
"Multiple recipients of PharmPK - Sent by"
Subject: Re: PharmPK Reference test substrate for CYP2C9
Date: Tue, 22 Jun 1999 23:44:23 -0500
Organization: Microsoft Corporation
X-Priority: 3
The widely accepted 2D6 substrates which you could use in man is
dextromethorphan, a safe anti-tussive agent. Dextromethorphan is metabolized
predominantly to detrorphan via 2D6. The ratio of dextromethorphan/total
dextrorphan (free+conjugate) is used as a measure of 2D6 activity for
phenotyping purpose. Measurement of this ratio in plasma is preferable to
the ratio in urine. I use this technique a great deal to find out if an
investigational drug is an inhibitor of 2D6 in man. I will be happy to
provide you some key references if you need.
Aziz Karim
---
Date: Wed, 23 Jun 1999 08:21:56 -0400
From: "Geraldine Ferron"
To: PharmPK.-a-.boomer.org
Subject: Re: PharmPK Reference test substrate for CYP2C9
Mime-Version: 1.0
Dear Erik,
You might want to use dextromethorphan (22 mg) and measure the
dextromethorphan/dextrorphan metabolic ratios in urine samples taken for a
subsequent 8 hr. Both analytes can be quantified by reversed-phase HPLC.
Dr. Geraldine Ferron
Wyeth-Ayerst Research
Clinical Pharmacokinetics
King of Prussia Road
Radnor PA, USA
---
From: DGarg8838.-at-.aol.com
Date: Wed, 23 Jun 1999 20:34:45 EDT
Subject: Re: PharmPK Reference test substrate for CYP2C9
To: PharmPK.at.boomer.org
MIME-Version: 1.0
We have used dextromethorphan for determining 2D6 metabolism. The test is
done by administering a cough syrup containing dextromethorphan and then
measure the ratio of the parent to desmethyl metabolite.
In a new protocol, we will use genotyping techniques to screen out slow
metabolizers for a pharmacokinetic study. There is a company by the name PPG=
x
in North Carolina who has the methodology for identifying various allels and
then predict the 2D6 phenotype status based on the genotype status. PPD
Pharmaco is exclusive marketer for PPGX and further information about this
company can be obtained from PPD.
Dyal Garg
Clinical Research Services, Inc.
8838 Indian River Run
Boynton Beach, FL 33437
Phone: 561-737-3954
Dgarg8838.aaa.aol.com
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Hello Erik:
The drug interaction guideline (CPMP/EWP/560/95) of the EMEA (www.eudra.org)
recommends for markers:
CYP2C9: S-warfarin and tolbutamide
CYP2C19: mefenytoin and omeprazole
Substrates, inhibitors and inducers are listed for the major drug metabolising
CYP450 enzymes.
Best wishes,
Jan-Georg
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