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Lars Weidolf - One of the best experts on this subject based on the ideXlab platform.
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comparison of inhibitory effects of the proton pump inhibiting drugs omeprazole esomeprazole lansoprazole pantoprazole and rabeprazole on human cytochrome p450 activities
Drug Metabolism and Disposition, 2004Co-Authors: Tommy B Andersson, Marie M Ahlstrom, Lars WeidolfAbstract:The human clearance of proton pump inhibitors (PPIs) of the substituted benzimidazole class is conducted primarily by the hepatic cytochrome P450 (P450) system. To compare the potency and specificity of the currently used PPIs (i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), we performed in vitro studies using human liver microsomal preparations and recombinant CYP2C19. Sample analysis was done using selected reaction monitoring liquid chromatography/tandem mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S-mephenytoin 4'-hydroxylation and R-omeprazole 5-hydroxylation, tested in either human liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition of CYP2C19 activity with K(i) of 0.4 to 1.5 microM for lansoprazole, 2 to 6 microM for omeprazole, approximately 8 microM for esomeprazole, 14 to 69 microM for pantoprazole, and 17 to 21 microM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4'-hydroxylation and CYP3A4-catalyzed midazolam 1'-hydroxylation (K(i) of 6 and 22 microM, respectively), which were at least 2 times more potent than the other PPIs. All PPIs were poor inhibitors of CYP2D6-mediated bufuralol 1'-hydroxylation with IC(50) > 200 microM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with K(i) values of 6 microM for CYP2C9, 2 to 8 microM for CYP2C19, 12 microM for CYP2D6, and 15 microM for CYP3A4. The inhibitory potency of R-omeprazole on the four studied P450 enzymes was also studied and showed higher inhibitory potency than its S-isomer on CYP2C9 and 2C19 activities. Our data suggest that, although the inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency compared with omeprazole and its R-enantiomer. The inhibitory potency of rabeprazole was relatively lower than the other PPIs, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.
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comparison of inhibitory effects of the proton pump inhibiting drugs omeprazole esomeprazole lansoprazole pantoprazole and rabeprazole on human cytochrome p450 activities
Drug Metabolism and Disposition, 2004Co-Authors: Xueqing Li, Tommy B Andersson, Marie M Ahlstrom, Lars WeidolfAbstract:The human clearance of proton pump inhibitors (PPIs) of the substituted benzimidazole class is conducted primarily by the hepatic cytochrome P450 (P450) system. To compare the potency and specificity of the currently used PPIs (i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), we performed in vitro studies using human liver microsomal preparations and recombinant CYP2C19. Sample analysis was done using selected reaction monitoring liquid chromatography/tandem mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S -mephenytoin 4′-hydroxylation and R -omeprazole 5-hydroxylation, tested in either human liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition of CYP2C19 activity with K i of 0.4 to 1.5 μM for lansoprazole, 2 to 6 μM for omeprazole, ∼8 μM for esomeprazole, 14 to 69 μM for pantoprazole, and 17 to 21 μM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4′-hydroxylation and CYP3A4-catalyzed midazolam 1′-hydroxylation ( K i of 6 and 22 μM, respectively), which were at least 2 times more potent than the other PPIs. All PPIs were poor inhibitors of CYP2D6-mediated bufuralol 1′-hydroxylation with IC 50 > 200 μM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with K i values of 6 μM for CYP2C9, 2 to 8 μM for CYP2C19, 12 μM for CYP2D6, and 15 μM for CYP3A4. The inhibitory potency of R -omeprazole on the four studied P450 enzymes was also studied and showed higher inhibitory potency than its S -isomer on CYP2C9 and 2C19 activities. Our data suggest that, although the inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency compared with omeprazole and its R -enantiomer. The inhibitory potency of rabeprazole was relatively lower than the other PPIs, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.
Omer I. Fantoukh - One of the best experts on this subject based on the ideXlab platform.
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safety assessment of phytochemicals derived from the globalized south african rooibos tea aspalathus linearis through interaction with cyp pxr and p gp
Journal of Agricultural and Food Chemistry, 2019Co-Authors: Vamshi K. Manda, Olivia R. Dale, Shabana I. Khan, Omer I. Fantoukh, Abidah Parveen, Mohammed F. Hawwal, Zulfiqar Ali, Amar G. ChittiboyinaAbstract:Rooibos tea ( Aspalathus linearis) is a well-known South African herbal tea enjoyed worldwide. Limited reports indicate the potential of rooibos tea to alter the activity of certain cytochrome P450 (CYP450) isozymes. In this study, the phytochemical investigation of MeOH extract of A. linearis (leaves and stems) resulted in the isolation and characterization of 11 phenolic compounds. The MeOH extract exhibited significant inhibition of the major human CYP450 isozymes (CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19). The strongest inhibition was observed by the extract for CYP3A4 (IC50 1.7 ± 0.1 μg/mL) followed by CYP2C19 (IC50 4.0 ± 0.3 μg/mL). Among the tested phytochemicals, the most potent inhibitors were isovitexin on CYP3A4 (IC50 3.4 ± 0.2 μM), vitexin on CYP2C9 (IC50 8.0 ± 0.2 μM), and thermopsoside on CYP2C19 (IC50 9.5 ± 0.2 μM). The two major, structurally related compounds aspalathin and nothofagin exhibited a moderate pregnane-X receptor (PXR) activation, which was associated with increased mRNA expression of CYP3A4 and CYP1A2, respectively. These results indicate that a high intake of nutraceuticals containing rooibos extracts may pose a risk of herb-drug interactions when consumed concomitantly with clinical drugs that are substrates of CYP enzymes.
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Safety Assessment of Phytochemicals Derived from the Globalized South African Rooibos Tea (Aspalathus linearis) through Interaction with CYP, PXR, and P‑gp
2019Co-Authors: Omer I. Fantoukh, Vamshi K. Manda, Olivia R. Dale, Shabana I. Khan, Abidah Parveen, Mohammed F. Hawwal, Zulfiqar Ali, Amar G. Chittiboyina, Alvaro Viljoen, Ikhlas A. KhanAbstract:Rooibos tea (Aspalathus linearis) is a well-known South African herbal tea enjoyed worldwide. Limited reports indicate the potential of rooibos tea to alter the activity of certain cytochrome P450 (CYP450) isozymes. In this study, the phytochemical investigation of MeOH extract of A. linearis (leaves and stems) resulted in the isolation and characterization of 11 phenolic compounds. The MeOH extract exhibited significant inhibition of the major human CYP450 isozymes (CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19). The strongest inhibition was observed by the extract for CYP3A4 (IC50 1.7 ± 0.1 μg/mL) followed by CYP2C19 (IC50 4.0 ± 0.3 μg/mL). Among the tested phytochemicals, the most potent inhibitors were isovitexin on CYP3A4 (IC50 3.4 ± 0.2 μM), vitexin on CYP2C9 (IC50 8.0 ± 0.2 μM), and thermopsoside on CYP2C19 (IC50 9.5 ± 0.2 μM). The two major, structurally related compounds aspalathin and nothofagin exhibited a moderate pregnane-X receptor (PXR) activation, which was associated with increased mRNA expression of CYP3A4 and CYP1A2, respectively. These results indicate that a high intake of nutraceuticals containing rooibos extracts may pose a risk of herb–drug interactions when consumed concomitantly with clinical drugs that are substrates of CYP enzymes
Joseph S Bertino - One of the best experts on this subject based on the ideXlab platform.
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combined phenotypic assessment of cytochrome p450 1a2 2c9 2c19 2d6 and 3a n acetyltransferase 2 and xanthine oxidase activities with the cooperstown 5 1 cocktail
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Siwaporn Chainuvati, Anne N Nafziger, Steven J Leeder, Andrea Gaedigk, Gregory L Kearns, Edward M Sellers, Yanhua Zhang, Angela D M Kashuba, Elizabeth Rowland, Joseph S BertinoAbstract:Previously, we have validated a 4-drug phenotyping cocktail, the “Cooperstown cocktail,” using caffeine (cytochrome P450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration–time curve from time 0 to infinity (P = .09), omeprazole metabolic ratio (P = .374), caffeine metabolic ratio (P = .169 for CYP1A2 activity), midazolam plasma clearance (P = .573), or dextromethorphan metabolic ratio (P = .747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO. Clinical Pharmacology & Therapeutics (2003) 74, 437–447; doi: 10.1016/S0009-9236(03)00229-7
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combined phenotypic assessment of cytochrome p450 1a2 2c9 2c19 2d6 and 3a n acetyltransferase 2 and xanthine oxidase activities with the cooperstown 5 1 cocktail
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Siwaporn Chainuvati, Anne N Nafziger, Steven J Leeder, Andrea Gaedigk, Gregory L Kearns, Edward M Sellers, Yanhua Zhang, Angela D M Kashuba, Elizabeth Rowland, Joseph S BertinoAbstract:Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.
Tommy B Andersson - One of the best experts on this subject based on the ideXlab platform.
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comparison of inhibitory effects of the proton pump inhibiting drugs omeprazole esomeprazole lansoprazole pantoprazole and rabeprazole on human cytochrome p450 activities
Drug Metabolism and Disposition, 2004Co-Authors: Tommy B Andersson, Marie M Ahlstrom, Lars WeidolfAbstract:The human clearance of proton pump inhibitors (PPIs) of the substituted benzimidazole class is conducted primarily by the hepatic cytochrome P450 (P450) system. To compare the potency and specificity of the currently used PPIs (i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), we performed in vitro studies using human liver microsomal preparations and recombinant CYP2C19. Sample analysis was done using selected reaction monitoring liquid chromatography/tandem mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S-mephenytoin 4'-hydroxylation and R-omeprazole 5-hydroxylation, tested in either human liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition of CYP2C19 activity with K(i) of 0.4 to 1.5 microM for lansoprazole, 2 to 6 microM for omeprazole, approximately 8 microM for esomeprazole, 14 to 69 microM for pantoprazole, and 17 to 21 microM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4'-hydroxylation and CYP3A4-catalyzed midazolam 1'-hydroxylation (K(i) of 6 and 22 microM, respectively), which were at least 2 times more potent than the other PPIs. All PPIs were poor inhibitors of CYP2D6-mediated bufuralol 1'-hydroxylation with IC(50) > 200 microM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with K(i) values of 6 microM for CYP2C9, 2 to 8 microM for CYP2C19, 12 microM for CYP2D6, and 15 microM for CYP3A4. The inhibitory potency of R-omeprazole on the four studied P450 enzymes was also studied and showed higher inhibitory potency than its S-isomer on CYP2C9 and 2C19 activities. Our data suggest that, although the inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency compared with omeprazole and its R-enantiomer. The inhibitory potency of rabeprazole was relatively lower than the other PPIs, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.
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comparison of inhibitory effects of the proton pump inhibiting drugs omeprazole esomeprazole lansoprazole pantoprazole and rabeprazole on human cytochrome p450 activities
Drug Metabolism and Disposition, 2004Co-Authors: Xueqing Li, Tommy B Andersson, Marie M Ahlstrom, Lars WeidolfAbstract:The human clearance of proton pump inhibitors (PPIs) of the substituted benzimidazole class is conducted primarily by the hepatic cytochrome P450 (P450) system. To compare the potency and specificity of the currently used PPIs (i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), we performed in vitro studies using human liver microsomal preparations and recombinant CYP2C19. Sample analysis was done using selected reaction monitoring liquid chromatography/tandem mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S -mephenytoin 4′-hydroxylation and R -omeprazole 5-hydroxylation, tested in either human liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition of CYP2C19 activity with K i of 0.4 to 1.5 μM for lansoprazole, 2 to 6 μM for omeprazole, ∼8 μM for esomeprazole, 14 to 69 μM for pantoprazole, and 17 to 21 μM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4′-hydroxylation and CYP3A4-catalyzed midazolam 1′-hydroxylation ( K i of 6 and 22 μM, respectively), which were at least 2 times more potent than the other PPIs. All PPIs were poor inhibitors of CYP2D6-mediated bufuralol 1′-hydroxylation with IC 50 > 200 μM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with K i values of 6 μM for CYP2C9, 2 to 8 μM for CYP2C19, 12 μM for CYP2D6, and 15 μM for CYP3A4. The inhibitory potency of R -omeprazole on the four studied P450 enzymes was also studied and showed higher inhibitory potency than its S -isomer on CYP2C9 and 2C19 activities. Our data suggest that, although the inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency compared with omeprazole and its R -enantiomer. The inhibitory potency of rabeprazole was relatively lower than the other PPIs, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.
Angela D M Kashuba - One of the best experts on this subject based on the ideXlab platform.
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lopinavir ritonavir induces the hepatic activity of cytochrome p450 enzymes cyp2c9 CYP2C19 and cyp1a2 but inhibits the hepatic and intestinal activity of cyp3a as measured by a phenotyping drug cocktail in healthy volunteers
Journal of Acquired Immune Deficiency Syndromes, 2006Co-Authors: Rosa F Yeh, Vincent E Gaver, Kristine B Patterson, Naser L Rezk, Faustina Baxtermeheux, Mike Blake, Joseph J Eron, Cheri E Klein, John C Rublein, Angela D M KashubaAbstract:Objective: The effect of lopinavir/ritonavir (LPV/r) administration on cytochrome P450 (CYP) enzyme activity was quantified using a phenotyping biomarker cocktail. Changes in CYP2C9, CYP2C19, CYP3A, CYP1A2, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) activities were evaluated using warfarin (WARF) + vitamin K, omeprazole (OMP), intravenous (IV) and oral (PO) midazolam (MDZ), and caffeine (CAF). Design: Open-label, multiple-dose, pharmacokinetic study in healthy volunteers. Methods: Subjects (n = 14) simultaneously received PO WARF 10 mg, vitamin K 10 mg, OMP 40 mg, CAF 2 mg/kg, and IV MDZ 0.025 mg/kg on days (D) 1 and 14, and PO MDZ 5 mg on D2 and D15. LPV/r (400/100 mg twice daily) was administered on D4- 17, CYP2C9 and CYP2C 19 activities were quantified by S-WARF AUC 0-inf and OMP/5-hydroxy OMP ratio, respectively. CYP1A2, NAT-2, and XO activities were quantified by urinary CAF metabolite ratios. Hepatic and intestinal + hepatic CYP3A activities were quantified by IV (CL) and PO (CL/F) MDZ clearance, respectively. Results: After LPV/r therapy, CYP2C9, CYP2C19, and CYP1A2 activity increased by 29%, 100%, and 43% (P = 0.001, 0.046, and 0.001), respectively. No changes were seen in NAT-2 or XO activity. Hepatic and intestinal + hepatic CYP3A activity decreased by 77% (P < 0.001) and 92% (P = 0.001), respectively. Conclusion: LPV/r therapy results in modest induction of CYP1A2 and CYP2C9 and potent induction of CYP2C19 activity. Increasing doses of concomitant medications metabolized by these enzymes may be necessary. LPV/r inhibited intestinal CYP3A to a greater extent than hepatic CYP3A activity. Doses of concomitant CYP3A substrates should be reduced when combined with LPV/r, although intravenously administered compounds may require less of a relative dose reduction than orally administered compounds.
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combined phenotypic assessment of cytochrome p450 1a2 2c9 2c19 2d6 and 3a n acetyltransferase 2 and xanthine oxidase activities with the cooperstown 5 1 cocktail
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Siwaporn Chainuvati, Anne N Nafziger, Steven J Leeder, Andrea Gaedigk, Gregory L Kearns, Edward M Sellers, Yanhua Zhang, Angela D M Kashuba, Elizabeth Rowland, Joseph S BertinoAbstract:Previously, we have validated a 4-drug phenotyping cocktail, the “Cooperstown cocktail,” using caffeine (cytochrome P450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration–time curve from time 0 to infinity (P = .09), omeprazole metabolic ratio (P = .374), caffeine metabolic ratio (P = .169 for CYP1A2 activity), midazolam plasma clearance (P = .573), or dextromethorphan metabolic ratio (P = .747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO. Clinical Pharmacology & Therapeutics (2003) 74, 437–447; doi: 10.1016/S0009-9236(03)00229-7
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combined phenotypic assessment of cytochrome p450 1a2 2c9 2c19 2d6 and 3a n acetyltransferase 2 and xanthine oxidase activities with the cooperstown 5 1 cocktail
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Siwaporn Chainuvati, Anne N Nafziger, Steven J Leeder, Andrea Gaedigk, Gregory L Kearns, Edward M Sellers, Yanhua Zhang, Angela D M Kashuba, Elizabeth Rowland, Joseph S BertinoAbstract:Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.
