Lauric acid as a model substrate for the simultaneous determination of cytochrome P450 2E1 and 4A in hepatic microsomes

Clarke, Stephen E.; Baldwin, Sandra; Bloomer, Jacqueline C.; Ayrton, Andrew D.; Sozio, Randall S.; Chenery, Richard J.

doi:10.1021/tx00042a018

Cited by 56 publications

(28 citation statements)

References 27 publications

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“…This substrate can also undergo -1-hydroxylation, preferentially carried out by CYP2E1 (Clarke et al, 1994). In the present study, CYP4A1 mRNA was only found in the liver.…”

Section: Downloaded Fromsupporting

confidence: 38%

Characterization of Microsomal Cytochrome P450-Dependent Monooxygenases in the Rat Olfactory Mucosa

Minn¹,

Pelczar²,

Denizot³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Nasal administration of a drug ensures therapeutic action by rapid systemic absorption and/or the entry of some molecules into the brain through different routes. Many recent studies have pointed out the presence of xenobiotic-metabolizing enzymes in rat olfactory mucosa (OM). Nevertheless, very little is known about the precise identity of isoforms of cytochrome P450 (P450)-dependent monooxygenases (P450) and their metabolic function in this tissue. Therefore, we evaluated mRNA expression of 19 P450 isoforms by semiquantitative reverse transcriptase-polymerase chain reaction and measured their microsomal activity toward six model substrates. For purposes of comparison, studies were conducted on OM and the liver. Specific activities toward phenacetin, chlorzoxazone, and dextromethorphan are higher in OM than in the liver; those toward lauric acid and testosterone are similar in both tissues, and that toward tolbutamide is much lower in OM. There are considerable differences between the two tissues with regard to mRNA expression of P450 isoforms. Some isoforms are expressed in OM but not in the liver (CYP1A1, 2G1, 2B21, and 4B1), whereas mRNA of others (CYP2C6, 2C11, 2D2, 3A1, 3A2, and 4A1) is present only in hepatic tissue. Although expression of CYP1A2, 2A1, 2A3, 2B2, 2D1, 2D4, 2E1, 2J4, and 3A9 is noticed in both tissues, there are a number of quantitative differences. On the whole, our results strongly suggest that CYP1A1, 1A2, 2A3, 2E1, 2G1, and 3A9 are among the main functional isoforms present in OM, at least regarding activities toward the six tested substrates. The implication of olfactory P450-dependent monooxygenases in toxicology, pharmacology, and physiology should be further investigated.

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“…This substrate can also undergo -1-hydroxylation, preferentially carried out by CYP2E1 (Clarke et al, 1994). In the present study, CYP4A1 mRNA was only found in the liver.…”

Section: Downloaded Fromsupporting

confidence: 38%

Characterization of Microsomal Cytochrome P450-Dependent Monooxygenases in the Rat Olfactory Mucosa

Minn¹,

Pelczar²,

Denizot³

et al. 2005

Drug Metab Dispos

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“…Standard assays were used to measure the activities of P450 isoenzymes in human liver microsomes and to investigate the effect of dabigatran etexilate, dabigatran, BIBR 951 CL, and BIBR 1987 SE on the various test reactions. CYP1A1 and CYP1A2 activity was measured by phenacetin O-deethylation (Tassaneeyakul et al, 1993), CYP2C19 and CYP2B6 by S-mephenytoin 4Ј-hydroxylation (Wedlund and Wilkinson, 1996) and N-dealkylation (Heyn et al, 1996), respectively, CYP2C9 by tolbutamide hydroxylation (Ludwig et al, 1998), CYP2D6 by bufuralol 1Ј-hydroxylation (Yamazaki et al, 1994), CYP2E1 and CYP4A11 by lauric acid 11-and 12-hydroxlation, respectively (Clarke et al, 1994;Amet et al, 1995), and CYP3A by nifedipine oxidation (Guengerich et al, 1986) and testosterone 6␤-hydroxylation (modified from the technique of Newton et al, 1995). All the incubations were performed in duplicate.…”

Section: Hplc Of Dabigatran and Metabolites In Incubatesmentioning

confidence: 99%

The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans

Blech¹,

Ebner²,

et al. 2007

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ABSTRACT:The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran ( Antithrombotic therapy plays an important role in the prevention and treatment of thromboembolic disorders. However, currently available agents are subject to certain limitations. Oral vitamin K antagonists, such as warfarin, have unpredictable pharmacokinetics and show numerous drug and food interactions (Ansell et al., 2004), whereas unfractionated and low molecular weight heparins and fondaparinux require parenteral administration. An orally active direct thrombin inhibitor would offer a number of potential advantages over these agents (Weitz and Bates, 2005).Dabigatran is a reversible, competitive, direct thrombin inhibitor that has been shown to be an effective antithrombotic agent in animal models (Stassen et al., 2001; Wienen et al., 2001a,b) and to be efficacious and safe in the prevention of deep vein thrombosis in patients undergoing elective total hip or knee replacement (Eriksson et al., 2005). Dabigatran etexilate is currently in Phase III development for primary prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery, acute VTE treatment, and VTE secondary prevention, as well as stroke prevention in patients with atrial fibrillation. Pharmacokinetic studies in healthy volunteers and orthopedic surgery patients showed that dose-dependent concentrations of dabigatran are achieved after p.o. administration of dabigatran etexilate, with peak concentrations reached after approximately 2 h and with a slight delay up to 6 h on the day of surgery (Eriksson et al., 2004(Eriksson et al., , 2005Stangier et al., 2005).This article describes a series of in vivo and in vitro studies performed to investigate the pharmacokinetics and metabolism of dabigatran in humans. ABBREVIATIONS: Dabigatran, -alanine, N-[[2-[[[4-[[[(hexyloxy) Materials and Methods Reference

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“…Standard assays were used to measure the activities of P450 isoenzymes in human liver microsomes and to investigate the effect of linagliptin on the various test reactions. Activities of CYP1A1 and CYP1A2 were measured by phenacetin O-deethylation (Tassaneeyakul et al, 1993); CYP2A6 was measured by by coumarin 7-hydroxylation (Pelkonen et al, 2000); CYP2C19 and CYP2B6 were measured by S-mephenytoin 4Ј-hydroxylation (Wedlund and Wilkinson, 1996) and N-dealkylation (Heyn et al, 1996), respectively; CYP2C8 was measured by by paclitaxel 6␣-hydroxylation (Cresteil et al, 1994); CYP2C9 was measured by tolbutamide hydroxylation (Ludwig et al, 1998); CYP2D6 was measured by bufuralol 1Ј-hydroxylation (Yamazaki et al, 1994); CYP2E1 and CYP4A11 were measured by lauric acid 11-and 12-hydroxylation, respectively (Clarke et al, 1994;Amet et al, 1995); and CYP3A was measured by nifedipine oxidation (Guengerich et al, 1986), testosterone 6␤-hydroxylation (modified from the technique of Newton et al, 1995), and midazolam 1-hydroxylation (Gorski et al, 1994). All incubations were performed in duplicate.…”

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confidence: 99%

The Metabolism and Disposition of the Oral Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, in Humans

Blech

Ludwig-Schwellinger²,

Gräfe-Mody³

et al. 2010

Drug Metab Dispos

172

161

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ABSTRACT:The pharmacokinetics and metabolism of linagliptin (BI1356, 8-(3R-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione) were investigated in healthy volunteers. Type 2 diabetes mellitus (T2DM) accounts for 90 to 95% of all diabetes cases and its incidence is increasing (Wild et al., 2004). The high frequency of complications associated with the disease leads to a significant reduction in life expectancy. One relatively new therapeutic option is the inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the rapid degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. After food intake, both hormones augment the action of insulin (Holst and Gromada, 2004;Mari et al., 2005;Drucker and Nauck, 2006;Drucker, 2007). The plasma half-life of GLP-1 is limited to a few minutes because of its rapid proteolytic degradation by DPP-4 (Graefe-Mody et al., 2009). Inhibitors of DPP-4 prolong the half-life of GLP-1 and glucose-dependent insulinotropic polypeptide, which leads to increases in glucose-dependent insulin secretion, inhibition of endogenous glucose production, decreased blood glucose, and the induction of feelings of satiety (Drucker, 2002;Nauck et al., 2003;Holst and Gromada, 2004).Linagliptin is a novel, orally active, highly specific, and potent inhibitor of DPP-4 that is currently in clinical development for the treatment of T2DM (Eckhardt et al., 2007;Fuchs et al., 2009b). Early clinical studies with linagliptin suggested a reduction in the glycated hemoglobin levels in patients with T2DM while maintaining a placebo-like safety and tolerability profile (Heise et al., 2009;Retlich et al., 2009). The pharmacokinetics of linagliptin were previously shown to be nonlinear due to target-mediated, concentrationdependent changes in binding to DPP-4 (Hüttner et al., 2008; Thomas et al., 2008a,b;Fuchs et al., 2009a;Heise et al., 2009).We report here a series of in vivo and in vitro studies performed to further establish the pharmacokinetics and metabolism of linagliptin in humans after intravenous and oral administration.Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.109.031476.ABBREVIATIONS: T2DM, type 2 diabetes mellitus; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; BI1355, 8-(3S-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione; CD1790, 7-but-2-ynyl-8-(3S-hydroxy-piperidin-1-yl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione; CD1789, 7-but-2-ynyl-8-(3R-hydroxy-piperidin-1-yl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione; CD10604, 7-but-2-yn-1-yl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-8-(3-oxopiperidin-1-yl)-3, 7-dihydro-1H-purine-2,6-dione; LOQ, lower limit of quantification; LC-MS/MS, liquid chromatography-tandem mass spectrometry; HPLC, high-performance liquid chromat...

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Lauric acid as a model substrate for the simultaneous determination of cytochrome P450 2E1 and 4A in hepatic microsomes

Cited by 56 publications

References 27 publications

Characterization of Microsomal Cytochrome P450-Dependent Monooxygenases in the Rat Olfactory Mucosa

Characterization of Microsomal Cytochrome P450-Dependent Monooxygenases in the Rat Olfactory Mucosa

The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans

The Metabolism and Disposition of the Oral Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, in Humans

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