Determination of a ‘GW cocktail’ of cytochrome P450 probe substrates and their metabolites in plasma and urine using automated solid phase extraction and fast gradient liquid chromatography tandem mass spectrometry

Scott, Rebecca J.; Palmer, James A.; Lewis, Ivor A. S.; Pleasance, Stephen

doi:10.1002/(sici)1097-0231(19991215)13:23<2305::aid-rcm790>3.0.co;2-g

Cited by 111 publications

(69 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16 The assay used atmospheric pressure ionization with turbo ion spray followed by multiple reaction monitoring of the characteristic deprotonated molecular ion to product-ion transitions for diclofenac and internal standard. This assay was linear from 25 to 30,000 ng/ml.…”

Section: Assay Methodology For Study 1 and Studymentioning

confidence: 99%

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

Mermelstein¹,

Hamilton²,

Wright

et al. 2013

Pharmacotherapy

View full text Add to dashboard Cite

STUDY OBJECTIVE To evaluate single-and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-b-cyclodextrin (HPbCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING Clinical research center. SUBJECTS Healthy adult volunteers. INTERVENTION Study 1: Subjects received HPbCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPbCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS Study 1: IV HPbCD-diclofenac had a higher peak plasma concentration (C max ) and earlier time to reach maximum plasma concentration (T max ), but equivalent plasma exposure (area under the curve from time zero to t [AUC 0-t ]) to IV Voltarol. The geometric mean ratio of HPbCD-diclofenac (IV) to Voltarol (IV) for AUC 0-t was 106.27%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IM) for AUC 0-t was 110.91%. The geometric mean ratio of HPbCD-diclofenac (IV) to HPbCD-diclofenac (IM) for AUC 0-t was 101.25%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IV) for AUC 0-t was 104.96%. Study 2: C max for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPbCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ngÁhour/ml) and 37.5 mg (1843 ngÁhour/ml) IV HPbCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ngÁhour/ml). CONCLUSIONS Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPbCD-diclofenac compared with Voltarol and after IM administration of HPbCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPbCD-diclofenac was equivalent to IV administration of HPbCD-diclofenac and IV administration of Voltarol. Study 2: HPbCDdiclofenac showed dose proportionality after single-and multiple-dose administration and no accumulation of HPbCD-diclofenac. HPbCD-diclofenac was safe and well tolerated following IV and IM administration.

show abstract

Section: Assay Methodology For Study 1 and Studymentioning

confidence: 99%

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

Mermelstein¹,

Hamilton²,

Wright

et al. 2013

Pharmacotherapy

View full text Add to dashboard Cite

show abstract

“…Microsomal production of 4-hydroxydebrisoquine was determined using an LC/MS/MS method described previously (Corchero et al, 2001) with a minor modification of liquid-liquid extraction (Pereira et al, 2000) rather than solid-phase extraction (Scott et al, 1999). Briefly, to the total microsomal incubations were added 20 l of internal standard solution (phenacetin, 5 g/ml in methanol), 500 l of propan-2-ol, 50 l of 0.4 M sodium hydroxide, and 3 ml of methyl tert-butyl ether.…”

Section: Methodsmentioning

confidence: 99%

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Granvil

Krausz²,

Gelboin³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

A panel of 15 recombinant cytochromes P450 expressed in human B-lymphoblastoid cells was used to study debrisoquine 4-hydroxylation. Both CYP2D6 and CYP1A1 carried out the reaction. The apparent K m (micromolar) and V max (picomoles per minute per picomole of P450) for CYP2D6 were 12.1 and 18.2 and for CYP1A1 were 23.1 and 15.2, respectively. CYP1A1 debrisoquine 4-hydroxylase was inhibited by the CYP1A1 inhibitor ␣-naphthoflavone and the CYP1A1 substrate 7-ethoxyresorufin. Additionally and surprisingly, this reaction was also inhibited by quinidine and quinine, with respective IC 50 values of 1.38 Ϯ 0.10 and 3.31 Ϯ 0.14 M, compared with those for CYP2D6 debrisoquine 4-hydroxylase of 0.018 Ϯ 0.05 and 3.75 Ϯ 2.07 M, respectively. Anti-CYP1A1 monoclonal antibody (mAb) 1-7-1 abolished CYP1A1 debrisoquine hydroxylase and anti-CYP2D6 mAb 50-1-3 eradicated CYP2D6 debrisoquine 4-hydroxylase. Three further CYP2D6-specific reactions were tested: dextromethorphan O-demethylation, bufuralol 1Ј-hydroxylation, and sparteine dehydrogenation. The CYP2D6 specificity, judged by the CYP2D6/CYP1A1 activity ratios was 18.5, 7.0, 6.0, and 1.6 for dextromethorphan, bufuralol, sparteine, and debrisoquine, respectively. Thus, debrisoquine is not a specific CYP2D6 substrate and quinidine is not a specific CYP2D6 inhibitor. These findings have significant implications for the conduct of in vitro drug metabolism inhibition studies and underscore the fallacy of "specific chemical inhibitors" of a supergene family of enzymes that have overlapping substrate specificities. The use of highly specific mAbs in such studies is mandated. It is unclear as yet whether these findings have implications for the relationship between CYP2D6 genotype and in vivo debrisoquine 4-hydroxylase activity.

show abstract

“…Plasma concentrations of chlorzoxazone and its 6-hydroxy metabolite (6-HC), caffeine and its metabolite 1,7-dimethylxanthine (DMX), and dapsone and its monoacetyl metabolite (MAD), as well as urine concentrations of dapsone and DHA, and mephenytoin and its 4-hydroxy metabolite (4-HM), were measured using an LC/MS/MS method described previously. 10 In plasma, caffeine and DMX were quantifiable to 0.02 lg/mL (precision within 10%, accuracy within 7% of nominal), chlorzoxazone and 6-HC were quantifiable to 0.1 lg/ mL (precision within 10%, accuracy within 5% of nominal), and dapsone and MAD were quantifiable to 0.25 lg/mL (precision within 13%, accuracy within 7% of nominal). In urine, dapsone and DHA were quantifiable to 0.1 lg/mL and 5 lg/mL, respectively (precision within 15%, accuracy within 12% of nominal), and mephenytoin and 4-HM were quantifiable to 0.1 lg/mL and 1 lg/mL, respectively (precision within 7%, accuracy within 10% of nominal).…”

Section: Bioanalysesmentioning

confidence: 99%

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Koch¹,

Corrigan²,

Manzo³

et al. 2004

Aliment Pharmacol Ther

View full text Add to dashboard Cite

SUMMARYAim: To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing. Methods: Thirty healthy men and women received 1 mg oral alosetron twice-daily for 29.5 days and a single oral dose of a metabolic probe cocktail before and on the last day of alosetron dosing. Serum alosetron concentrations were measured on days 1, 8, 15, 22 and 29. Probe-substrate and metabolite concentrations were measured after each cocktail dose. Results: Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probemetabolite/substrate ratios associated with CYP2C19, 2E1, 2C9, or 3A4 activity, but modestly decreased those associated with CYP1A2 and N-acetyltransferase activity. Systemic exposure to alosetron was higher in women, positively correlated with age and body mass index, and negatively correlated with CYP1A2 activity. Incidence of constipation was higher in women, but not associated with alosetron concentration. Conclusions: Single dose data can reliably predict the pharmacokinetics of alosetron after repeated doses. Alosetron exhibits limited potential for inhibition of cytochrome P450-mediated metabolism. Interindividual differences in alosetron pharmacokinetics associated with demographic factors may be related to strong dependence on metabolism by CYP1A2.

show abstract

Determination of a ‘GW cocktail’ of cytochrome P450 probe substrates and their metabolites in plasma and urine using automated solid phase extraction and fast gradient liquid chromatography tandem mass spectrometry

Cited by 111 publications

References 20 publications

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Contact Info

Product

Resources

About