Lidocaine metabolism

CYP3A4 i Lidocaine metabolism to MEGX Plasma concentrations of MEGX severe cirrhosis = 4.6 ng/mL moderate cirrhosis = 19.1 ng/mL mild cirrhosis = 32.8 ng/mL control = 53.4 ng/mL Hence the more severe the cirrhosis the lower the metabolism of lidocaine to MEGX due to 4- CYP3A4 [44]... 

Orlando R, Piccoli P, De Martin S, Padrini R, Ploreani M, Palatini P. Cytochrome P50 1A2 is a major determinant of lidocaine metabolism in vivo Effects of liver ftmction. Clin Pharmacol Ther 2004 75 80-8. 

Shiffman, M.L., Luketic, V.A., Sanyal, A.J., Duckworth, P.F., Purdum, RR, Contas, M.J., Scott Mills, A., Edinboro, L.E., PokUs, A. Hepatic lidocaine metabolism and liver histology in patients with chronic hepatitis and cirrhosis. Hepatology 1994 19 933-940... 

Li AP, Rasmussen A, Xu L, et al. Rifampicin induction of lidocain metabolism in cultured human hepatocytes. / Pharmacol Exp Ther. 1995 274 673-677. 

Imaoka S, Enomotl K, Oda Y, et al. Lidocaine metabolism by human cytochrome P-450s purified from hepatic microsomes comparison of those with rat hepatic cytochrome P-450s. J Pharmacol Exp Ther 1990 255 1385-1391. 

Bargetzi MJ, Aoyama T, Gonzalez FJ, Meyer UA. Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4. Clin Pharmacol Ther 1989 46 521 527. 

Inomata S, Nagashima A, Osaka Y, Kazama T, Tanaka E, Sato S, Toyooka H Propofol inhibits lidocaine metabolism in human and rat liver microsomes. JAnesfft (2003) 17,246-50. 

Nakayama S, Miyabe M, Kakiuchi Y, Inomata S, Osaka Y, Fukuda T, Kohda Y, Toyodca H. Propofol does not inhibit lidocaine metabolic during epidural anesthesia. Ane Analg (2004)99,1131-5. 

Inomata S, Naga iima A Osaka Y, Tanaka E, Toyooka H. Effects of clonidine on lidocaine metabolism in human or rat liver microscnies.J.<4/i 5 (2003) 17,281-3. 

An in vitro study has demonstrated that amiodarone may inhibit lidocaine metabolism competitively and vice versa. The interaction in vivo may be due to inhibition of the cytochrome P450 isoenzyme CYP3A4 hy amiodarone and/or its main metabolite desethylamiodarone. CYP3A4 is partially involved in the metabolism of lidocaine. 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

Another topical anesthetic, similar to benzocaine, is lidocaine, which is used to relieve the pain of shingles (herpes zoster) infections. Lidocaine is called an amide anesthetic, because it is not an ester (the alcohol is replaced by an amide, the nitrogen group). Amide anesthetics are metabolized by the liver, and are less prone to cause allergic reactions. If an anesthetic has the letter i in the prefix (lidocaine, prilocaine, bupivacaine), it is an amide anesthetic. 

A. G. De Boer, D. D. Breimer, H. Mattie, J. Pronk, and J. M. Gubbens-Stibbe, Rectal bioavailability of lidocaine in man Partial avoidance of first-pass metabolism, Clin. Pharmacol. Ther, 26, 701-709 (1979). 

Work out all of the possible metabolites of lidocaine. Start at the top of the molecule and work toward the other end of it. Just work with one position at a time and do not worry about all of the products that involve combinations of metabolism at two different positions there are plenty of metabolites without considering such combinations. 

Chemicals that are metabolized rapidly by the liver cannot be given for systemic effect by the enteral route because the portal circulation carries them directly to the liver. For example, lidocaine, a drug of value in controlling cardiac arrhythmias, is absorbed well from the gut, but is completely inactivated in a single passage through the liver. 

Fig. 4.5. Major routes of metabolism for lidocaine (4.128). Direct hydrolysis yields 2,6-dimethylaniline (2,6-xylidine, 4.129) and 2-(diethylamino)acetic acid (diethylglycine, 4.130). Hydrolysis of the metabolites monoethylglycinexylidine (4.131) and glycinexylidine (4.132) also yields 4.129. The metabolites 4.131 and 4.132 also undergo hydroxylation at the aromatic ring to form 4.133 and 4.134, respectively, which, in turn, are hydrolyzed to 4-hydroxy-2,6-dimethylaniline (4.135). This compound can also be formed by oxidation of 4.129. 

After oral administration of ameltolide (4.143, Fig. 4.6) to rats, no hydrolytic products were detected in biological fluids [103], One could argue that the two o-Me groups afforded steric protection to the amide bond. However, steric hindrance may not be the main reason for the absence of metabolic cleavage in this compound, since, for lidocaine (4.12, Fig. 4.5), cleavage of the amide bond represents a major metabolic route in mammals. The apparent absence of hydrolysis in the metabolism of ameltolide may be caused by the predominance of major alternative pathways, namely A-acetylation and hydroxylation. Furthermore, the small fraction of unidentified polar metabolites may contain some products of hydrolysis. 

Figure 12.3. Metabolism of lidocaine to MEGX (in nmol MEGX mg" wet weight liver slice) in liver slices after different incubation times (h). p < 0.05 versus shaken flask, rocker platform, roller system and six-well shaker. p < 0.05 versus shaken flask, rocker platform and six-well shaker. Data are the mean of three separate experiments SEM.

MEGX is readily detected by HPLC and fluorescence polarization immunoassay techniques [14,21,25,40,41]. The test is simple, normally requiring a onetime blood sampling, and informative because it depends on the capacity of the hepatic enzymes to metabolize lidocaine. While the analysis of lidocaine metabolites is rapid, this method has not been adapted for continuous hepatic function monitoring, which may be possible with the radiolabeled analogues such as Tc-Sn-lidocaine iminodiacetic acid [42]. 

Amide-type agents include articaine, lidocaine, bupivacaine, prilocaine, mepivacain and ropiva-caine. These are metabolized in the liver by microsomal enzymes with amidase activity. The amide group is preferred for parenteral and local use. If by accident rapidly administered intravascularly these agents, especially bupivacaine but also lidocaine, can produce serious and potentially lethal adverse effects including convulsions and cardiac arrest. They can more easily accumulate after multiple administrations. Intravenous lidocaine is sometimes used for regional anesthesia, for infiltration procedures, for the induction of nerve blockade and for epidural anesthesia. However, it is also used as an antiarrhythmic. Bupivacaine is a long-acting local anesthetic used for peripheral nerve blocks and epidural anesthesia. 

C. Adenosine is a product of the metabolism of adenosine triphosphate. Phenytoin and lidocaine are totally synthetic, while digoxin occurs naturally in plants and quinine occurs in the cinchona tree. 

Y. Azuma, K. Ohura (2004). Immunological modulation by lidocaine-epinephrine and prilocaine-felypressin on the functions related to natural immunity in neutrophils and macrophages. Curr. Drug Targ. Immune, Endocr. Metabol. Disord. 4 29-36. 

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