Characterization of lidocaine metabolism by rat nasal microsomes: implications for nasal drug delivery

Deshpande, V. S.; Genter, Mary Beth; Jung, Chul-Ho; Desai, Pankaj B.

doi:10.1007/bf03190366

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…Antibodies raised against CYP2A (Su et al, 1996) or CYP2B (Wardlaw et al, 1998) have been used in OM, but their lack of specificity precluded accurate P450 identification. Even after a 35-cycle amplification, we did not observe any expression of mRNA coding for CYP2C6, 2C11, 2D2, 3A1, 3A2, and 4A1 in OM, although Western blot experiments showed that CYP2C11 and 3A2 proteins were present in very low quantities in OM (Deshpande et al, 1999;Genter et al, 2002). The conflicting results concerning CYP3A may be explained by the observations of Aiba et al (2003): their work demonstrated the existence of an immunological cross-reaction between CYP3A2 and CYP3A9; the mRNA of the latter was clearly detected in OM in the present study.…”

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confidence: 57%

“…In OM, we detected the mRNA coding for CYP1A1, 1A2, 2A3, 2E1, 2G1, 2J4, and 4B, the expression of which had already been described by others at the protein level (Chen et al, 1992;Zhang et al, 1997;Wardlaw et al, 1998;Deshpande et al, 1999;Genter et al, 2002) or at the mRNA level (Nef et al, 1989;Zhang et al, 1997;Longo et al, 2000;Wang et al, 2002;Robottom-Ferreira et al, 2003). In addition, we identified for the first time the mRNA coding for CYP2A1, 2B2, 2B21, 2D1, 2D4, and 3A9.…”

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confidence: 55%

“…They observed that P450 activities in OM were of the same order of magnitude as or higher than those in the liver. Several P450s present in the liver were also revealed by Western blot or immunohistochemistry in OM: CYP1A1/2, CYP2B1, CYP2C, CYP2E1, CYP2J4, and CYP3A1 (Chen et al, 1992;Zhang et al, 1997;Wardlaw et al, 1998;Deshpande et al, 1999;Genter et al, 2002). CYP2A3 protein, weakly expressed in the liver, is largely expressed in olfactory tissues (Chen et al, 1992).…”

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confidence: 98%

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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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confidence: 57%

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confidence: 55%

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confidence: 98%

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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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“…We recently showed that metabolism of lidocaine to MEGX was catalyzed by microsomes prepared either from nasal olfactory or respiratory mucosa [21]. This was of interest to us for several reasons.…”

Section: Introductionmentioning

confidence: 99%

Induction of olfactory mucosal and liver metabolism of lidocaine by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

Genter

Apparaju

Desai

2002

J Biochem & Molecular Tox

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Formulation of drugs for administration via the nasal cavity is becoming increasingly common. It is of potential clinical relevance to determine whether intranasal drug administration itself, or exposure to other xenobiotics, can modulate the levels and/or activity of nasal mucosal metabolic enzymes, thereby affecting the metabolism and disposition of the drug. In these studies, we examined changes in several of the major metabolic enzymes in nasal epithelial tissues upon exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as well as the impact of these changes on the metabolism of a model intranasally administered drug, lidocaine. Results of these studies show that TCDD can induce multiple metabolic enzymes in the olfactory mucosa and that the pattern of induction in the olfactory mucosa does not necessarily parallel that which occurs in the liver. Further, increases in enzyme levels noted by Western blot analysis were associated with increased activities of several nasal mucosal enzymes as well as with enhanced conversion of lidocaine to its major metabolite, monoethyl glycine xylidide (MEGX). These results demonstrate that environmental exposures can influence the levels and activity of nasal mucosal enzymes and impact the pharmacology of drugs administered via the nasal route.

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“…However, most substrate probes of the CYP450 superfamily are non-specific for the recognition of the enzymes although selectivity is apparent for some compounds (6)(7); and the majority of CYP450s expressed in the hepatic microsome have been found in extrahepatic tissues (8)(9)(10), where xenobiotics are transformed into active intermediates or inactive metabolites as in liver. So far, the metabolic capacity of phenacetin O-deethylase(s) in the extrahepatic tissues is unknown for lack of a suitable methodology.…”

Section: Introductionmentioning

confidence: 99%

PhenacetinO-deethylation in extrahepatic tissues of rats

Cui

Luo

et al. 2002

Eur. J. Drug Metab. Pharmacokinet.

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Phenacetin O-deethylation is a marker reaction of CYP450 1A2 activity. The drug-metabolizing enzyme is constitutively expressed in liver. In this study, an in vivo rat model for assessment of extrahepatic metabolism was used to investigate phenacetin O-deethylation and the alterations in the disposition of phenacetin due to the loss of liver function. Rats were divided into the model and normal control groups. The model was established according to our previously described method. The concentrations of phenacetin and its major metabolites acetaminophen, glucuronate-acetaminophen and sulfate-acetaminophen in plasma and urine were determined by HPLC. 30 min after intravenous administration of 0.16% phenacetin 10 mg x kg(-1), plasma acetaminophen in the model group was only 3.6% of that in the control group (0.09+/-0.04 microg x mL(-1) vs 2.49+/-0.85 microg x mL(-1), n = 8). 30 min after intragastric injection of 0.4% phenacetin 30 mg x kg(-1), plasma acetaminophen formation was very slight, about 8.6% of plasma phenacetin in the model group (0.74+/-0.43 microg x mL(-1) acetaminophen vs 8.57+/-8.42 microg x mL(-1) phenacetin) and 6.8% in the control group (1.06+/-0.59 microg x mL(-1) acetaminophen vs 15.47+/-7.21 microg x mL(-1) phenacetin, n = 8); no significant differences were observed in plasma phenacetin, total acetaminophen and the ratio of acetaminophen to phenacetin between control and model groups. In the urine collected for 3 h after intravenous administration of 0.16% phenacetin 10 mg x kg(-1), the total recovery of acetaminophen (as free, glucuronate- and sulfate-acetaminophen ) in the model group was 4.6% of that in the control group (4.47+/-4.27 microg vs 96.63+/-8.50 microg, n = 6), but phenacetin recovery in the model group was 9 times higher than that in the control group (15.03+/-17.72 microg vs 1.66+/-0.50 microg). The results indicate that phenacetin O-deethylation in the extrahepatic tissues and the first-pass metabolism of the probe compound seem to be negligible in rats, but the renal excretion of phenacetin, as a compensation, dramatically increases in model rats.

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Characterization of lidocaine metabolism by rat nasal microsomes: implications for nasal drug delivery

Cited by 8 publications

References 26 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

Induction of olfactory mucosal and liver metabolism of lidocaine by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

PhenacetinO-deethylation in extrahepatic tissues of rats

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