Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin

In an in vitro study, we compared the cytochrome P450 (CYP)-dependent metab olism and drug interactions of the acid and lactone forms of the 3-hydroxy- 3-methylglutaryl (HMG)-CoA reductase inhibitor atorvastatin. Metabolism of atorvastatin acid and lactone by human liver microsomes resulted in para-hy droxy and ortho-hydroxy metabolites. Both substrates were metabolized mainl y by CYP3A4 and CYP3A5. Atorvastatin lactone had a significantly higher aff inity to CYP3A4 than the acid (K-m : para-hydroxy atorvastatin, 25.6 +/- 5. 0 mu M; para-hydroxy atorvastatin lactone, 1.4 +/- 0.2 mu M; ortho-hydroxy atorvastatin, 29.7 +/- 9.4 mu M; and ortho-hydroxy atorvastatin lactone, 3. 9 +/- 0.2 mu M). Compared with atorvastatin acid, CYP-dependent metabolism of atorvastatin lactone to its para-hydroxy metabolite was 83-fold higher [ formation CLint (V-max /K-m): lactone 2949 +/- 3511 versus acid 35.5 +/- 48 .1 mu l . min(-1) . mg(-1)] and to its ortho-hydroxy metabolite was 20-fold higher (CLint: lactone 923 +/- 965 versus acid 45.8 +/- 59.1 mu l . min(-1 ) . mg(-1)). Atorvastatin lactone inhibited the metabolism of atorvastatin acid by human liver microsomes with an inhibition constant (K-i) of 0.9 mu M while the K-i for inhibition of atorvastatin by atorvastatin lactone was 90 mu M. Binding free energy calculations of atorvastatin acid and atorvast atin lactone complexed with CYP3A4 revealed that the smaller desolvation en ergy of the neutral lactone compared with the anionic acid is the dominant contribution to the higher binding affinity of the lactone rather than an e ntropy advantage. Because atorvastatin lactone has a significantly higher m etabolic clearance and the lactone is a strong inhibitor of atorvastatin ac id metabolism, it can be expected that metabolism of the lactone is the rel evant pathway for atorvastatin elimination and drug interactions. We hypoth esize that most of the open acid metabolites present in human plasma are ge nerated by interconversion of lactone metabolites.