PharmPK Discussion - Cocktail to study CYP inhibition

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On 24 Mar 2004 at 14:48:10, "Vernon Gray" (vernon_g.at.hotmail.com) sent the message


One of our drugs is an inhibitor of several CYP isozymes.  I would like
to do a study using a cocktail approach for this.  Can anyone share
their exeperience about CRO's they have used for this and substrates
for CYP3A4, 2D6, 2C9, and 2C19.  Apparently there is some debate about
ideal substrates for these.
Thanks,
Vernon

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On 25 Mar 2004 at 08:54:12, (mahmud.2.kajbaf.aaa.gsk.com) sent the message

Vernon,
There is article using a cocktail approach by Elizabeth A. Dierks et
al., (2001), Drug Metabolism and Disposition, Vol 29, No.1, pp23-29.
Regards
Mahmud Kajbaf , PhD
  Medicines Research Centre
  Via A. Fleming, 4
  37135 Verona
  Italy
  Tel: +39 045 9219104
  Fax: +39 045 9218153
  E-Mail: mahmud.2.kajbaf.-at-.gsk.com

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On 25 Mar 2004 at 09:44:29, "Paula Macedo Cerqueira" (Paula.Cerqueira.-at-.anvisa.gov.br) sent the message


Vernon
I am pointing out some CYP's substrates but it is very important to
investigate if they are good substrates for your population, 'cause
genetic differences make them good markers not for all populations
studied.
CYP3A4:  midazolam to 1-hydroxymidazolam
CYP2C9:  tolbutamide to carboxitolbutamide
CYP2C19: mephenitoin to 4 hydroxymephenitoin or S/R-mephenitoin ratio
CYP2D6:  debrisoquine to 4-hydroxydebrisoquine
	     metoprolol to alpha-hydroxymetoprolol
With regards,
Paula Macedo Cerqueira, PhD
Pharmacist- Technical Consultant
Nacional Health Surveillance Agency - ANVISA
Management of Generic Drugs - GEMEG
Bioequivalence Unity - S\0x201Eo Paulo -SP- Brazil

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On 25 Mar 2004 at 14:57:45, uceph hijazi (uceph_hijazi.-at-.yahoo.fr) sent the message


Dear Vernon,
Multi-probe cocktail is a practical approach, however
some points should be carefully considered:
1-Selectivity of probe substrates
2-Lack of pharmacokinetic and pharmacodynamic
interactions between probes
3-Safety of simultaneous administration
Please find below some references:
Pittsburgh 5-drug cocktail (Frye RF et al., 1997)
Caffeine, chlorzoxazone, dapsone, debrisoquine,
mephenytoin
CYP1A2, CYP2E1, CYP3A, NAT, CYP2D6, CYP2C19
Karolinska 5-drug cocktail (Christensen M et al. ,
2003)
Caffeine, losartan, omeprazole, debrisoquine, quinine
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4
Cooperstown 4-drug cocktail (Streeman D et al, 2000)
Caffeine, omeprazole, dextromethorphan, midazolam
CYP1A2, CYP2C19, CYP2D6, CYP3A, NAT-2, XO
Cooperstown (5+1)-drug cocktail (Chainuvati S et al.
2003)
caffeine, dextromethorphan, omeprazole, midazolam and
warfarin + vitamin K
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT-2, XO
5-drug cocktail (Blakey GE et al., 2003)
Caffeine, tolbutamide, debrisoquine, chlorzoxazone,
midazolam
CYP1A2, CYP2C9 CYP2D6, CYP2E1, CYP3A
Youssef Hijazi
H\0xD9pital neurologique et neurochirurgicale
Service Pharmaceutique
Laboratoire de Pharmacocin\0xC8tique Clinique
B.P. Lyon Montchat 69394 Lyon Cedex 03-FRANCE
Tel: 04 72 35 72 45

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On 25 Mar 2004 at 09:04:34, "Fadiran, Emmanuel O" (FADIRANE.-a-.cder.fda.gov) sent the message


I recommend you read the manuscript published by PhRMA in Drug
Metabolism &
Disposition 31:815-832, 2003 (Title: The conduct of in vitro and in vivo
drug-drug interaction studies: A Pharmaceutical Research and
Manufacturers
of America (PhRMA) Perspective).
Thanks.
Tayo
Emmanuel Olutayo Fadiran, R.Ph.,Ph.D.
Team Leader, Pulmonary & Allergy Drug Products Team
HFD-870, Office of Clinical Pharmacology & Biopharmaceutics
FDA, 5600 Fisher's Lane, Rockville, MD 20857.
Phone - 301-827-1076
Fax - 301-827-1271.
email: fadirane.-a-.cder.fda.gov

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