Involvement of CYP1A2 in mexiletine metabolism

Nakajima, Miki; Kobayashi, Kaoru; Shimada, Noriaki; Tokudome, Shogo; Yamamoto, Toshinori; Kuroiwa, Yukio

doi:10.1046/j.1365-2125.1998.00048.x

Cited by 67 publications

(39 citation statements)

References 25 publications

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“…Coumarin 7-hydroxylation was determined as described previously (Ohyama et al, 2000). The substrate concentration was 0.1 to 5 M. Ethoxyresorufin O-deethylation and methoxyresorufin O-demethylation were determined as described previously (Nakajima et al, 1998). The concentrations of ethoxyresorufin and methoxyresorufin were 0.1 to 2.5 M for CYP1A1 and CYP1A2 or 0.5 to 7.5 M for CYP2A6 and CYP2A13.…”

Section: Methodsmentioning

confidence: 99%

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

Fukami¹,

Nakajima²,

Sakai³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Human cytochrome CYP2A13 shows overlapping substrate specificity with CYP2A6, catalyzing the metabolism of coumarin, nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Recently, it was found that CYP2A13 could catalyze the metabolic activations of 4-aminobiphenyl and aflatoxin B 1 , which are known to be catalyzed by human CYP1A2. In the present study, we investigated the substrate specificity of CYP2A13. It was shown that CYP2A13 could catalyze ethoxyresorufin O-deethylation, methoxyresorufin O-demethylation, and phenacetin O-deethylation, which are used as marker activities for human CYP1A2. Although the intrinsic clearances (V max /K m ) of the two former reactions by CYP2A13 were much lower than that of CYP1A2, the value of the last reaction by CYP2A13 was 2-fold higher than that of CYP1A2.Of particular interest was that CYP2A13 has higher affinity toward phenacetin than CYP1A2. In contrast, CYP2A6 hardly catalyzed these reactions, although the amino acid identity with CYP2A13 is as high as 93.5%. Furthermore, we found that CYP2A13 can catalyze theophylline 8-hydroxylation and 3-demethylation, which are known to be mainly catalyzed by human CYP1A2, although the intrinsic clearances were approximately one-tenth that of CYP1A2. CYP2A13 would not contribute to the systemic clearance of these drugs because CYP2A13 is hardly expressed in human liver. However, it may play a role in metabolism in local tissues such as lung or trachea. In conclusion, the results of the present study could extend our understanding of the substrate specificity of CYP2A13.

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Section: Methodsmentioning

confidence: 99%

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

Fukami¹,

Nakajima²,

Sakai³

et al. 2006

Drug Metab Dispos

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“…The reason for this result might be due to the similar K m values of CYPs, perhaps CYP2C6 and CYP2C11 for the 6-HNA formation activities. [22][23][24] We also investigated which CYP isoform(s) is involved in the 6-O-demethylation of 6-MNA in pooled human liver microsomes. CYP2C9 was identified as the major isoform involved in the oxidation of 6-MNA by human liver microsomes on the basis of the following lines of evidence.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Characterization of the Cytochrome P450 Isoforms Involved in the Metabolism of 6-Methoxy-2-napthylacetic Acid, an Active Metabolite of the Prodrug Nabumetone

Matsumoto

Nemoto

Hasegawa

et al. 2011

Biological & Pharmaceutical Bulletin

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Nabumetone, 4-(6-methoxy-2-naphthyl)-butan-2-one, is a nonsteroidal anti-inflammatory drug (NSAID) that has proved effective in the treatment of rheumatoid and osteoarthritis.1) Nabumetone is a prodrug that undergoes extensive first-pass metabolism to 6-methoxy-2-naphthylacetic acid (6-MNA), the major circulating metabolite. 6-MNA is largely responsible for the therapeutic efficacy of nabumetone. It decreases prostaglandin synthesis via inhibition of cyclooxygenase, an enzyme involved in the arachidonic acid conversion pathway.2)The metabolism of 6-MNA has been studied in rats, the major experimental animal, and humans. The primary metabolite of 6-MNA, namely, 6-hydroxy-2-naphthylacetic acid (6-HNA), was detected in urine. About 70% of a radiolabeled dose of nabumetone was recovered within 48 h in urine, mainly as 6-MNA, 6-HNA and their conjugates.3) The 6-O-demethylation of 6-MNA to 6-HNA is known to be a major metabolic pathway (Fig. 1). Although it may be obvious that the cytochrome P450 (CYP) system is involved in this pathway, actual CYP isoforms that are involved have not been identified. Their identification is of considerable clinical importance with regard to potential drug interactions and genetically based individual variations of drug metabolism. To our knowledge, no in vitro study has been conducted with respect to the metabolism of 6-MNA or to obtain specific data on the enzyme(s) involved in its metabolic pathway in vitro using human and rat liver microsomes.The purpose of this study was to elucidate CYP isoforms with regard to the 6-O-demethylase activity, a major metabolic pathway of 6-MNA, in human/rat microsomes and recombinant human CYP enzymes expressed in insect cells in which both human/rat CYP and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-P450 reductase cDNAs had been incorporated. We also examined the inhibition or activation of 6-MNA metabolism by chemical substrates and antibodies. MATERIALS AND METHODSChemicals and Reagents 6-MNA and 6-HNA were supplied by Sanwa Kagaku Kenkyusho (SKK) Co., Ltd. (Nagoya, Japan). Glucose-6-phosphaste and glucose-6-dehydrogenase were obtained from Oriental Yeast (Tokyo, Japan). NADPH and nicotinamide adenine dinucleotide phosphate (NADP) were purchased from Alexis (San Diego, CA, U.S.A.). Mefenamic acid and naproxen were purchased from Tokyo Kasei Kogyo Co. (Tokyo, Japan). Acetonitrile, methanol and cimetidine were purchased from Wako Pure Chemical Industries Ltd. (Tokyo, Japan). Furafylline, troleandomycin, ketoconazole, sulfaphenazole and S-mephenytoin were purchased from Daiichi Pure Chemicals (Tokyo, Japan). Diethyldithiocarbamate and quinidine were pur- The cytochrome P450 (CYP) isoforms that catalyze the oxidation metabolism of 6-methoxy-2-napthylacetic acid (6-MNA), an active metabolite of nabumetone, were studied in rats and humans. Using an extractive reversed-phase HPLC assay with fluorescence detection, monophasic Michaelis-Menten kinetics was obtained for the formation of 6-hydroxy-2-naphthylacetic acid (6-HNA) in liver micr...

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“…Their contributions were estimated to be CYP1A2：CYP2D6＝28％：72％ for propranolol and 18％：82％ for mexiletine. 18,19) For the above-mentioned drugs, estimation by the ePPBD and estimation by the conventional BSAbased method were compared, using the population mean oral CL ( Â CL (PO) ) and standard D C (predetermined dose) for references.…”

Section: ×00001mentioning

confidence: 99%

Estimating Pediatric Doses of Drugs Metabolized by Cytochrome P450 (CYP) Isozymes, Based on Physiological Liver Development and Serum Protein Levels

et al. 2010

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We established a method for estimating pediatric doses of drugs metabolized by cytochrome P450 (CYP) isozymes, using the free fraction of drug in plasma ( fu), serum protein level (P ), liver volume (LV ), and CYP activity (Vmax/ Km) as indices of physiological and biochemical development in children up to 15 years old. This method allows the child/adult dose ratio (D C /D A )＝child/adult oral clearance ratio (CL (PO)C /CL (PO)A ) of drugs mainly metabolized in the liver to be estimated by the following equation:Major metabolism of drugs was ascribed to CYP1A2 for theophylline and caŠeine, and CYP1A2 and CYP2D6 for propranolol and mexiletine. For theophylline and caŠeine, CL (PO)C /CL (PO)A calculated from the child/adult body surface area ratio (BSA ratio) and the value calculated by our method were compared, using Â CL (PO)C / Â CL (PO)A calculated from the clearance ratio based on population pharmacokinetics (PPK ratio) as a reference. For all drugs, pediatric doses calculated from the Crawford equation and our equation were compared, with predetermined doses as the reference. For theophylline and caŠeine, the relative accuracy of our method was signiˆcantly higher than that of BSA-based estimation when the PPK ratio was used for reference. For theophylline, caŠeine, and propranolol, the relative accuracy of our method was signiˆcantly higher than that of BSA-based estimation when predetermined doses were used for reference. Theseˆndings indicate the validity of our method which considers the physiological and biochemical development (i.e., fu, P, LV, and CYP activity) for pediatric dose estimation.

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Involvement of CYP1A2 in mexiletine metabolism

Cited by 67 publications

References 25 publications

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

In Vitro Characterization of the Cytochrome P450 Isoforms Involved in the Metabolism of 6-Methoxy-2-napthylacetic Acid, an Active Metabolite of the Prodrug Nabumetone

Estimating Pediatric Doses of Drugs Metabolized by Cytochrome P450 (CYP) Isozymes, Based on Physiological Liver Development and Serum Protein Levels

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