Kinetic analysis of mutual metabolic inhibition of lidocaine and propranolol in rat liver musomes

Suzuki, Tomohiko; Ishida, Ryosuke; Matsui, Shin Ichi; Masubuchi, Yuji; Narimatsu, Shizuo

doi:10.1016/0006-2952(93)90055-2

Cited by 9 publications

(6 citation statements)

References 13 publications

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“…These changes are due to a reduction of the intrinsic clearance of lignocaine as well as hepatic blood flow (Tucker et al 1984). Because propranolol does not affect the formation of monoethylglycinexylidide but inhibits the 3-hydroxylation of lignocaine (Suzuki et al 1993), we may postulate that 3-hydroxylation is important in the human metabolism of lignocaine. Because 3-hydroxylation is mediated by CYPlA2 (Imaoka rt al.…”

Section: Discussionmentioning

confidence: 98%

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Isohanni¹,

Neuvonen

Olkkola³

1999

Pharmacology & Toxicology

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Absiruct: Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(O-m)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P

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Section: Discussionmentioning

confidence: 98%

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Isohanni¹,

Neuvonen

Olkkola³

1999

Pharmacology & Toxicology

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“…Otton et al showed that oxidative metabolism of lidocaine in rat liver microsomes was inhibited by various hblockers, including propranolol (Otton et al, 1984). Suzuki et al demonstrated that propranolol competitively inhibited the liver microsomal oxidation of lidocaine (Suzuki et al, 1993). Further data (Bowdle et al, 1987) indicated a substantial reduction in bupivacaine clearance, supporting the hypothesis that propranolol inhibits amide local anesthetic metabolism within the hepatocyte.…”

Section: Discussionmentioning

confidence: 96%

“…Lidocaine is avidly metabolized by mammalian liver and extrahepatic tissues (Benowitz and Meister, 1978;Oda et al, 1989) and cytochromes P-450 2B1, P-450 4B1 and P-450 3A4 in microsomes contribute to the metabolism of lidocaine to a monoethylglycinexylidide and 3-hydroxy lidocaine (Bargetzi et al, 1989;Oda et al, 1989). The roles of cytochrome P-450-linked monooxygenase systems in the metabolism of amines, including lidocaine and propranolol, and the metabolic interaction between lidocaine and propranolol have been studied extensively (Otton et al, 1984;Al-Asady et al, 1989;Suzuki et al, 1993). However, the role of FAD-containing monooxygenase (FMO) in the metabolism of these drugs has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Porcine FAD-containing monooxygenase metabolizes lidocaine, bupivacaine and propranolol in vitro

Liao

Tomita

et al. 2004

Life Sciences

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“…4,5) Although PL itself was demonstrated to inhibit CYP-dependent drug-metabolism, 6,7) an inhibitory mechanism was proposed in which a reactive metabolic intermediate of PL covalently bound to CYP species catalyzing PL ring-hydroxylations. 8,9) 4-OH-PL, one of major metabolites of PL, is a pharmacologically active metabolite whose β-blocking activity is almost equivalent to the parent compound.…”

Section: Introductionmentioning

confidence: 99%

Effects of Pretreatment of Hep G2 Cells with .BETA.-Naphthoflavone on Cytotoxicity of Propranolol and its Active Metabolite 4-Hydroxypropranolol

Miyano

Motoyama

Fukuoka

et al. 2003

JOURNAL OF HEALTH SCIENCE

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Cytotoxicities of propranolol (PL) and its active metabolite, 4-hydroxypropranolol (4-OH-PL), were examined in a human hepatoma cell line, Hep G2. Hep G2 cells were cultured in the presence of β-naphthoflavone (BNF, 25 or 50 µM), lansoprazole (LPZ, 25 or 50 µM) or 0.5% dimethylsulfoxide (vehicle) for 48 hr. The cells were harvested, and microsomal and cytosolic fractions were prepared by differential centrifugation methods. Various enzyme activities were determined as follows: microsomal 7-ethoxyresorufin (ER) O-deethylation as a CYP1A1 index, microsomal phenacetin (PN) O-deethylation as a CYP1A2 index, microsomal and cytosolic p-nitrophenyl acetate (NPA) hydrolysis as a carboxylesterase index and cytosolic 4-OH-PL sulfation as a sulfotransferase index. The pretreatment of Hep G2 cells with LPZ or BNF increased microsomal ER O-deethylase activities, and the potency of BNF was much higher than that of LPZ. Cytosolic 4-OH-PL sulfation was also elevated by the pretreatment with BNF but not with LPZ. Microsomal PN O-deethylase activity was not detectable in either the control or BNFpretreated group under the conditions used. Microsomal and cytosolic NPA hydrolase activities were similar between the control and the BNF-pretreated groups. Cytotoxicities of PL and 4-OH-PL were attenuated in BNFpretreated Hep G2 cells compared to non-pretreated Hep G2 cells. These results suggest that increased activities of microsomal CYP1A1 and cytosolic sulfotransferases by pretreatment with BNF may contribute to the attenuating the cytotoxicity of PL and 4-OH-PL in Hep G2 cells, at least in part.

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Kinetic analysis of mutual metabolic inhibition of lidocaine and propranolol in rat liver musomes

Cited by 9 publications

References 13 publications

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Porcine FAD-containing monooxygenase metabolizes lidocaine, bupivacaine and propranolol in vitro

Effects of Pretreatment of Hep G2 Cells with .BETA.-Naphthoflavone on Cytotoxicity of Propranolol and its Active Metabolite 4-Hydroxypropranolol

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