Species differences and interindividual variation in liver microsomal cytochrome P450 2A enzymes: Effects on coumarin, dicumarol, and testosterone oxidation

Pearce, Robin E.; Greenway, Denise; Parkinson, Andrew

doi:10.1016/0003-9861(92)90115-d

Cited by 172 publications

(90 citation statements)

References 56 publications

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“…These compounds and the P450 primarily inhibited included coumarin (500 M) for CYP2A6, sulfaphenazole (10 M) for CYP2C9, S-mephenytoin (250 M) for CYP2C19, quinidine (10 M) for CYP2D6, or ketoconazole (2 M) for CYP3A. Two mechanism-based inhibitors were also examined for their ability to inhibit this reaction: furafylline (10 M) for CYP1A2 or DDC (300 M) for CYP2E1 (Pearce et al, 1992;Wrighton et al, 1993;Newton et al, 1995;Gorski et al, 1997). These compounds, except for coumarin, were also examined for their effect on N-desmethylatomoxetine formation.…”

Section: Methodsmentioning

confidence: 99%

Identification of the Human Cytochromes P450 Responsible for Atomoxetine Metabolism

Ring

Gillespie²,

Eckstein³

et al. 2002

Drug Metab Dispos

171

179

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ABSTRACT:Studies were performed to determine the human enzymes responsible for the biotransformation of atomoxetine to its major metabolite, 4-hydroxyatomoxetine, and to a minor metabolite, N-desmethylatomoxetine. Utilizing human liver microsomes containing a full complement of cytochrome P450 (P450) enzymes, average K m and CL int values of 2.3 M and 103 l/min/mg, respectively, were obtained for 4-hydroxyatomoxetine formation. Microsomal samples deficient in CYP2D6 exhibited average apparent K m and CL int values of 149 M and 0.2 l/min/mg, respectively. In a human liver bank characterized for P450 content, formation of 4-hydroxyatomoxetine correlated only to CYP2D6 activity. Of nine expressed P450s examined, 4-hydroxyatomoxetine was formed at a rate 475-fold greater by CYP2D6 compared with the other P450s. These results demonstrate that CYP2D6 is the enzyme primarily responsible for the formation of 4-hydroxyatomoxetine. Multiple P450s were found to be capable of forming 4-hydroxyatomoxetine when CYP2D6 was not expressed. However, the efficiency at which these enzymes perform this biotransformation is reduced compared with CYP2D6. The formation of the minor metabolite Ndesmethylatomoxetine exhibited average K m and CL int values of 83 M and 0.8 l/min/mg, respectively. Utilizing studies similar to those outlined above, CYP2C19 was identified as the primary enzyme responsible for the biotransformation of atomoxetine to Ndesmethylatomoxetine. In summary, CYP2D6 was found to be the primary P450 responsible for the formation of the major oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine. Furthermore, these studies indicate that in patients with compromised CYP2D6 activity, multiple low-affinity enzymes will participate in the formation of 4-hydroxyatomoxetine. Therefore, coadministration of P450 inhibitors to poor metabolizers of CYP2D6 substrates would not be predicted to decrease the clearance of atomoxetine in these individuals.Atomoxetine (Fig. 1) (formally known as tomoxetine; LY139603) is under development as a therapeutic agent for the treatment of attention deficit hyperactivity disorder in children and adults. Atomoxetine enhances norepinephrine function through a highly selective blockade of the presynaptic norepinephrine transporter and has low affinities for other neuronal transporters or neurotransmitter receptor sites (Wong et al., 1982;Gehlert et al., 1993). This is an interesting and potentially important new drug since it is likely to be the first approved treatment for attention deficit hyperactivity disorder that is not a psychostimulant. Studies with this compound in healthy human volunteers (Farid et al., 1985) showed that the clearance of atomoxetine exhibited a bimodal distribution, suggesting that an enzyme that exhibits a genetic polymorphism was involved in the metabolism of atomoxetine. The study further reported that in both extensive and poor metabolizers of atomoxetine, para-hydroxyatomoxetine (later definitively identified as 4-hydroxyatomoxetine) was the major oxidative metabo...

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Section: Methodsmentioning

confidence: 99%

Identification of the Human Cytochromes P450 Responsible for Atomoxetine Metabolism

Ring

Gillespie²,

Eckstein³

et al. 2002

Drug Metab Dispos

171

179

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“…Japan: Lake, 1987;Pearce et al, 1992). Aniline p-hydroxylation was assayed colorimetrically with a Hitachi U-1000 spectrophotometer (Hitachi; Imai et al 1966).…”

Section: Methodsmentioning

confidence: 99%

“…CYPIA2) (Guengerich et al 1982). coumarin 7-hydroxylation (CYP2A6) (Pearce et al 1992). aniline p-hydroxylation (CYP2EI) (Ryan et al 1985) and (±)-bufuralol l'-hydroxylation (CYP2D6) (Nakamura et al 1996 calculated by the peak height of the metabolite using a standard curve generated by the authentic standard.…”

mentioning

confidence: 99%

Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral platinum agent

Ando

Shimizu²,

Nakamura³

et al. 1998

Br J Cancer

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Summary Bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV) (Fukuoka et al. 1991: McGuire et al. 1996. These agents available today are. however, generally administered intravenously. The development of an oral platinum drug has been desired to improve the quality of life of patients receiving cancer chemotherapy in terms of easy administration. Bis-acetato-ammine-dichloro-cvclohexylamineplatinum (IV). JM2 16. is the first oral antineoplastic platinum agent currently under development. In preclinical studies. JM' 16 exhibited in vitro and in vivo anti-tumour efficacy comparable with cisplatin and carboplatin. and an activity against cell lines that were resistant to cisplatin (Kelland et al. 1993). Several phase H clinical trials of JM216 monotherapy have already been performed in the United States and Europe. and a phase I study has finished in Japan (Groen et al. 1996: Fujii et al. 1997: Peereboom et al. 1997. Further, some combination regimens of JM216 with other anti-tumour agents. such as taxans. can be expected. but no information on the potential dru2 interactions bet-een JM2 16 and other drugs has been reported.The metabolic pathway of the drug is complicated and has not been well understood (Raynaud et al. 1996). However, there are some implications that metabolism of JM216 might affect drugmetabolizing enzymes in the liver. First. at least six metabolites were detected in plasma samples from patients who received JM216 (Raynaud et al. 1996). Four of them were also obtained by in mvitro incubations with fresh human plasma. whereas the

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“…Coumarin 7-hydroxylation activity was determined as described previously (Greenlee and Poland, 1978;Pearce et al, 1992).…”

Section: Materials Pilocarpine Hydrochloride and [Imidazol-2-mentioning

confidence: 99%

Involvement of CYP2A6 in the Formation of a Novel Metabolite, 3-Hydroxypilocarpine, from Pilocarpine in Human Liver Microsomes

Endo¹,

Ban²,

Hirata³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Pilocarpine is a cholinergic agonist that is metabolized to pilocarpic acid by serum esterase. In this study, we discovered a novel metabolite in human urine after the oral administration of pilocarpine hydrochloride, and we investigated the metabolic enzyme responsible for the metabolite formation. The structure of the metabolite was identified as 3-hydroxypilocarpine by liquid chromatography-tandem mass spectrometry and NMR analyses and by comparing to the authentic metabolite. To clarify the human cytochrome P450 (P450) responsible for the metabolite formation, in vitro experiments using P450 isoform-selective inhibitors, cDNAexpressed human P450s (Supersomes; CYP1A2, -2A6, -2B6, -2C9, -2C19, -2D6, -2E1, and -3A4), and liver microsomes from different donors were conducted. The formation of 3-hydroxypilocarpine in human liver microsomes was strongly inhibited (>90%) by 200 M coumarin. Other selective inhibitors of CYP1A2 (furafylline and ␣-naphthoflavone), CYP2C9 (sulfaphenazole), CYP2C19 [(S)-mephenytoin], CYP2E1 (4-methylpyrazole), CYP2D6 (quinidine), and CYP3A4 (troleandomycin) had a weak inhibitory effect (<20%) on the formation. The highest formation activity was expressed by recombinant CYP2A6. The K m value for recombinant CYP2A6 was 3.1 M, and this value is comparable with that of human liver microsomes (1.5 M). The pilocarpine 3-hydroxylation activity was correlated with coumarin 7-hydroxylation activity in 16 human liver microsomes (r ‫؍‬ 0.98). These data indicated that CYP2A6 is the main enzyme responsible for the 3-hydroxylation of pilocarpine. In conclusion, we identified a novel metabolite of pilocarpine, 3-hydroxypilocarpine, and we clarified the involvement of CYP2A6 in the formation of this molecule in human liver microsomes.

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Species differences and interindividual variation in liver microsomal cytochrome P450 2A enzymes: Effects on coumarin, dicumarol, and testosterone oxidation

Cited by 172 publications

References 56 publications

Identification of the Human Cytochromes P450 Responsible for Atomoxetine Metabolism

Identification of the Human Cytochromes P450 Responsible for Atomoxetine Metabolism

Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral platinum agent

Involvement of CYP2A6 in the Formation of a Novel Metabolite, 3-Hydroxypilocarpine, from Pilocarpine in Human Liver Microsomes

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