Studies on sulfation of synthesized metabolites from the local anestheticsropivacaine and lidocaine using human cloned sulfotransferases

The metabolism of the local anesthetics lidocaine and ropivacaine (ropi) in volves several steps in humans. Lidocaine is mainly hydrolyzed and hydroxyl ated to 4-OH-2,6-xylidine (4-OH-xyl). The metabolism of ropi, involving dea lkylation and hydroxylation, gives rise to 3-OH-ropi, 4-OH-ropi, 3-OH-2'6'- pipecoloxylidide (3-OH-PPX), and 5-OH-methyl-ropi. Because the metabolites are hydroxylated, they are particularly prone to subsequent Phase II conjug ation reactions such as sulfation and glucuronidation. This study focused o n the in vitro sulfation of these metabolites as well as another suspected metabolite of ropi, 2-carboxyl-ropi. All the metabolites were synthesized f or the subsequent enzymatic studies. Five cloned human sulfotransferases (S Ts) 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 huma n liver. The results demonstrate that all of the metabolites except 2-OH-me thyl-ropi and 2-carboxyl-ropi can be sulfated. It was also found that all o f 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-r opi, and 4-OH-ropi whereas ST1B2 sulfates only 4-OH-xyl. The most extensive ly sulfated ropi metabolite is 3-OH-PPX, In conclusion, all of the hydroxyl ated metabolites of lidocaine and ropi can be sulfated if the hydroxyl grou p is attached to the aromatic ring in the metabolites. The human ST enzymes that are considered to be responsible for the sulfation of these metabolit es 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 by Halldin et at. (1996).