Lumiracoxib has been associated with bioactivation resulting in the formation of a toxic intermediate leading to drug associated liver damage. Lumiracoxib--an NSAID CH3 Show a structural formula to indicate how lumiracoxib could be metabolized and bioactivated into a reactive NAPQI-like reactive intermediate that will account for its liver toxicity. Remember that in CYP450 catalyzed phase 1 drug metabolism the para- hydroxylation of an aromatic amine (an aniline derivative) is a very common metabolic reaction. If lumiracoxib was first p-hydroxylated the the p-hydroxylated product again oxidized by CYP 450what might result? Use the production of NAPQI that I presented as a model for the 2nd step.

(a) Which of the following drugs is more hydrolytically labile? Briefly explain. OH H OH مممممم CO₂H Clavulanic acid Loperamide (b) For each of the above drugs, indicate ONE functional group that is prone to oxidation. (c) One of the degradation products of clavulanic acid in an acidic environment is the following: HO₂C OH HN CO₂H Draw the mechanism of this degradation reaction.

Chlorophyll, heme, vitamin B12, and a host of other substances are synthesized from porphobilinogen, which is itself formed from the condensation of two molecules of 5-aminolevulinate. The two 5-aminolevulinates are bound to lysine (Lys) residues in the enzyme, one in the enamine form and the other in the imine form. Condensation is thought to occur via a several step process, one of which is shown below. ÇO2 ÇO2 CO2 + NH3 NH3 H H3N 5-aminolevulinate (enamine form) 5-aminolevulinate (imine form) Porphobilinogen Draw curved arrows to illustrate the movement of electrons in this step of the reaction. Arrow-pushing Instructions CO2 CO2 CO2 CO2 :B BH* H-A H3N H3Ņ

9 HW Chapter 19 - Selected Exercises Question 2 of 8 0.6/1 (d) CH,CO3H Product(s): Draw Your Solution Save for Later Attempts: 0 of 3 used Submit Answer MacBook Air A) F12 F11 F10 F9 F7 delete & 8 Y enter II