1. Artelinic acid (AL), a water-soluble artemisinin analogue for treatment of multidrug resistant malaria, is metabolized to the active metabolite dihydroqinghaosu (DQHS) solely by CYP3A4/5. Although AL is not metabolized by CYP2C9, it does inhibit diclofenac 4-hydroxylase activity with an IC50 = 115 microM. Interestingly, AL activates CYP2D6-mediated bufuralol metabolism in human liver microsomes but not recombinant CYP2D6-Val by approximately 30% at AL concentrations up to 100 microM. 2. In human liver microsomes, AL is metabolized to DQHS with a Km = 157 +/- 44 microM and Vmax = 0.77 +/- 0.56 nmol DQHS/min/mg protein. Human recombinant CYP3A4 catalysed the conversion of AL to DQHS with a Km = 102 +/- 23 microM and a Vmax = 1.96 +/- 0.38 nmol DQHS/min/nmol P450. The kinetic parameters (Km and Vmax) for DQHS formation from CYP3A5 were 189 +/- 19 microM and 3.60 +/- 0.42 nmol DQHS/min/nmol P450 respectively. 3. Inhibition studies suggest that azole antifungals and calcium channel blockers may present clinically significant drug drug interactions. In human liver microsomes, ketoconazole and miconazole were potent competitive inhibitors of DQHS formation with a Ki = 0.028 and 0.124 microM respectively. Verapamil is a non-competitive inhibitor of DQHS formation in human liver microsomes with a Ki = 15 microM.
The separation of enantiomerically and diastereomerically related stereoisomers of acylated Asp-Phe dipeptides was explored using capillary electrophoresis (CE). This series of dipeptides included the alpha-L,L parent compound and the three other potential Asp containing stereoisomers (alpha-D,D, alpha-L,D, and alpha-D,L), as well the four possible isoAsp containing stereoisomers (beta-L,L, beta-D,D, beta-L,D and beta-D,L). The separation of these substances was explored using both neutral and charged cyclodextrins as the stereoisomer selector added to the running electrolyte. The major experimental parameters investigated included pH, the cyclodextrin type, and the cyclodextrin concentration. Due to differences in the pKa values of the carboxylic acid groups, adjustment of the separation buffer to between pH 3.0 and 4.0 provided for sufficient electrophoretic mobility differences to result in excellent separations of the diastereomerically related peptides in this pH region. The resolution of the enantiomerically related peptide stereoisomers was accomplished using low concentrations (1 mM) of the anionic cyclodextrin derivative, sulfobutylether-beta-cyclodextrin (SBE-beta-CD). This negatively charged cyclodextrin was found to be superior for the resolution of the enantiomerically related peptides as compared to native beta-cyclodextrin or the neutral derivatives, dimethyl beta-cyclodextrin and hydroxypropyl beta-cyclodextrin. An alternative approach using anionic or neutral surfactants in conjunction with the SBE-beta-CDs was also explored and found to be successful but problematic.
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