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Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots.

Bosilkovska M, Samer CF, Déglon J, Rebsamen M, Staub C, Dayer P, Walder B, Desmeules JA, Daali Y - Clin. Pharmacol. Ther. (2014)

Bottom Line: In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin.The pharmacokinetic profiles of the drugs were comparable in DBS and plasma.Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.

ABSTRACT
The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.

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Metabolic ratio profiles after oral administration of cocktail capsule alone (diamonds), with an inhibitor (squares), or with an inducer (triangles) in dried blood spots. *P < 0.05; **P < 0.01. dor/dem: continuous lines are used for extensive metabolizers (EMs) and dashed lines for intermediate metabolizers (IMs). bup, bupropion; caf, caffeine; dem, dextromethorphan; dor, dextrorphan; mdz, midazolam; OH-bup, 4-hydroxybupropion; OH-flb, 4-hydroxyflurbiprofen; flb, flurbiprofen; OH-mdz, 1-hydroxymidazolam; OH-opz, 5-hydroxyomeprazole; opz, omeprazole; par, paraxanthine.
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fig3: Metabolic ratio profiles after oral administration of cocktail capsule alone (diamonds), with an inhibitor (squares), or with an inducer (triangles) in dried blood spots. *P < 0.05; **P < 0.01. dor/dem: continuous lines are used for extensive metabolizers (EMs) and dashed lines for intermediate metabolizers (IMs). bup, bupropion; caf, caffeine; dem, dextromethorphan; dor, dextrorphan; mdz, midazolam; OH-bup, 4-hydroxybupropion; OH-flb, 4-hydroxyflurbiprofen; flb, flurbiprofen; OH-mdz, 1-hydroxymidazolam; OH-opz, 5-hydroxyomeprazole; opz, omeprazole; par, paraxanthine.

Mentions: The DBS concentration ratios of metabolite/probe (metabolic ratios (MRs)) at each sampling time point after oral administration of the cocktail, alone and with pretreatment, are shown in Figure 3. Statistically significant differences among the sessions for every sampling point were observed for OH-bup/bup, OH-flb/flb, and dor/dem MRs. OH-mdz/mdz MRs at the inhibition and induction sessions statistically differed from those of the cocktail-alone session at every sampling point for which the substances could be quantified (0.5–3 h). Most significant statistical differences (P < 0.01) in OH-opz/opz MRs were observed 2, 3, and 4 h after cocktail administration. MRs of par/caf significantly decreased at each time point for the inhibition session. At the induction session, a tendency toward an increase in MRs was observed, but the difference was statistically significant (P < 0.05) only 4 h after cocktail administration.


Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots.

Bosilkovska M, Samer CF, Déglon J, Rebsamen M, Staub C, Dayer P, Walder B, Desmeules JA, Daali Y - Clin. Pharmacol. Ther. (2014)

Metabolic ratio profiles after oral administration of cocktail capsule alone (diamonds), with an inhibitor (squares), or with an inducer (triangles) in dried blood spots. *P < 0.05; **P < 0.01. dor/dem: continuous lines are used for extensive metabolizers (EMs) and dashed lines for intermediate metabolizers (IMs). bup, bupropion; caf, caffeine; dem, dextromethorphan; dor, dextrorphan; mdz, midazolam; OH-bup, 4-hydroxybupropion; OH-flb, 4-hydroxyflurbiprofen; flb, flurbiprofen; OH-mdz, 1-hydroxymidazolam; OH-opz, 5-hydroxyomeprazole; opz, omeprazole; par, paraxanthine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151019&req=5

fig3: Metabolic ratio profiles after oral administration of cocktail capsule alone (diamonds), with an inhibitor (squares), or with an inducer (triangles) in dried blood spots. *P < 0.05; **P < 0.01. dor/dem: continuous lines are used for extensive metabolizers (EMs) and dashed lines for intermediate metabolizers (IMs). bup, bupropion; caf, caffeine; dem, dextromethorphan; dor, dextrorphan; mdz, midazolam; OH-bup, 4-hydroxybupropion; OH-flb, 4-hydroxyflurbiprofen; flb, flurbiprofen; OH-mdz, 1-hydroxymidazolam; OH-opz, 5-hydroxyomeprazole; opz, omeprazole; par, paraxanthine.
Mentions: The DBS concentration ratios of metabolite/probe (metabolic ratios (MRs)) at each sampling time point after oral administration of the cocktail, alone and with pretreatment, are shown in Figure 3. Statistically significant differences among the sessions for every sampling point were observed for OH-bup/bup, OH-flb/flb, and dor/dem MRs. OH-mdz/mdz MRs at the inhibition and induction sessions statistically differed from those of the cocktail-alone session at every sampling point for which the substances could be quantified (0.5–3 h). Most significant statistical differences (P < 0.01) in OH-opz/opz MRs were observed 2, 3, and 4 h after cocktail administration. MRs of par/caf significantly decreased at each time point for the inhibition session. At the induction session, a tendency toward an increase in MRs was observed, but the difference was statistically significant (P < 0.05) only 4 h after cocktail administration.

Bottom Line: In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin.The pharmacokinetic profiles of the drugs were comparable in DBS and plasma.Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.

ABSTRACT
The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.

Show MeSH
Related in: MedlinePlus