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Research ArticleArticle

Studies on Sulfation of Synthesized Metabolites from the Local Anesthetics Ropivacaine and Lidocaine Using Human Cloned Sulfotransferases

Charles N. Falany, Josie L. Falany, Jin Wang, Johan Hedström, Hans von Euler Chelpin and Stellan Swedmark
Drug Metabolism and Disposition September 1999, 27 (9) 1057-1063;
Charles N. Falany
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Josie L. Falany
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Jin Wang
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Johan Hedström
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Hans von Euler Chelpin
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Stellan Swedmark
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Abstract

The metabolism of the local anesthetics lidocaine and ropivacaine (ropi) involves several steps in humans. Lidocaine is mainly hydrolyzed and hydroxylated to 4-OH-2,6-xylidine (4-OH-xyl). The metabolism of ropi, involving dealkylation and hydroxylation, gives rise to 3-OH-ropi, 4-OH-ropi, 3-OH-2′6′-pipecoloxylidide (3-OH-PPX), and 2-OH-methyl-ropi. Because the metabolites are hydroxylated, they are particularly prone to subsequent Phase II conjugation reactions such as sulfation and glucuronidation. This study focused on the in vitro sulfation of these metabolites as well as another suspected metabolite of ropi, 2-carboxyl-ropi. All the metabolites were synthesized for the subsequent enzymatic studies. Five cloned human sulfotransferases (STs) were used in this study, namely, the phenol-sulfating form of ST (P-PST-1), the monoamine-sulfating form of ST (M-PST), estrogen-ST (EST), ST1B2, and dehydroepiandrosterone-ST (DHEA-ST), all of which are expressed in human liver. The results demonstrate that all of the metabolites except 2-OH-methyl-ropi and 2-carboxyl-ropi can be sulfated. It was also found that all of the STs can conjugate the remaining hydroxylated metabolites except DHEA-ST. However, there are large differences in the capacity of the individual human ST isoforms to conjugate the different metabolites. P-PST-1 sulfates 3-OH-PPX, 3-OH-ropi, and 4-OH-xyl; M-PST and EST conjugate 3-OH-PPX, 3-OH-ropi, and 4-OH-ropi whereas ST1B2 sulfates only 4-OH-xyl. The most extensively sulfated ropi metabolite is 3-OH-PPX. In conclusion, all of the hydroxylated metabolites of lidocaine and ropi can be sulfated if the hydroxyl group is attached to the aromatic ring in the metabolites. The human ST enzymes that are considered to be responsible for the sulfation of these metabolites in vivo are P-PST-1, M-PST, EST, and ST1B2. These enzymes are also found in the liver; this is the most important tissue for the metabolism of ropi in humans, demonstrated byHalldin et al. (1996).

Footnotes

  • Send reprint requests to: Stellan Swedmark, Ph.D., Dept. of Pharmacokinetics and Biopharmaceutics, Astra Pain Control AB, S-151 85 Södertälje, Sweden. E-mail:stellan.swedmark{at}pain.se.astra.com or Dr. Charles Falany, Dept. of Pharmacology, University of Alabama at Birmingham, UAB Sta., Birmingham, AL 35294-0001. E-mail: charles.falany{at}ccc.uab.edu

  • ↵2 The GenBank accession numbers for the human ST sequences are: DHEA-ST, L20000; P-PST-1, L19999; ST1B2, U95726; EST,S77383, M-PST, U08032; MS, mass spectroscopy; TSP, thermospray.

  • Abbreviations used are::
    PPX
    2′,6′-pipecoloxylidide
    ST
    sulfotransferase
    PAPS
    3′-phosphoadenosine 5′-phosphate
    ropi
    ropivacaine
    EtOH
    ethanol
    MeOH
    methanol
    EtOAc
    ethyl acetate
    Et2O
    diethyl ether
    4-OH-xyl
    4-OH-2,6-xylidine
    P-PST-1
    phenol-sulfating form of PST
    M-PST
    monoamine-sulfating form of PST
    DHEA-ST
    dehydroepiandrosterone-ST
    • Received November 16, 1998.
    • Accepted May 27, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (9)
Drug Metabolism and Disposition
Vol. 27, Issue 9
1 Sep 1999
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Research ArticleArticle

Studies on Sulfation of Synthesized Metabolites from the Local Anesthetics Ropivacaine and Lidocaine Using Human Cloned Sulfotransferases

Charles N. Falany, Josie L. Falany, Jin Wang, Johan Hedström, Hans von Euler Chelpin and Stellan Swedmark
Drug Metabolism and Disposition September 1, 1999, 27 (9) 1057-1063;

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Research ArticleArticle

Studies on Sulfation of Synthesized Metabolites from the Local Anesthetics Ropivacaine and Lidocaine Using Human Cloned Sulfotransferases

Charles N. Falany, Josie L. Falany, Jin Wang, Johan Hedström, Hans von Euler Chelpin and Stellan Swedmark
Drug Metabolism and Disposition September 1, 1999, 27 (9) 1057-1063;
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