DFT study on hydroxy acid–lactone interconversion of statins: the case of atorvastatin

Abstract

Atorvastatin (ATV), the best known HMG-CoA reductase inhibitor family member, undergoes pH-dependent hydroxy acid-lactone interconversion similar to other statins. Although the only active form is a linear one, it was shown that drug interactions should also be considered for the lactone. The ATV lactonisation-hydrolysis mechanism was investigated theoretically using the density functional theory (DFT) method. Under both mildly acidic and basic conditions, the ATV lactone form is less stable than its hydroxy acid form. However, in the presence of a carboxylic acid, the equilibrium was only slightly shifted towards the lactone side (4 kcal mol(-1) difference between the substrate and the product), while energy gain for the hydrolysis under basic conditions amounts to 18 kcal mol(-1). Hydrolysis activation energy barriers were 19 and 6 kcal mol(-1), in acidic and basic conditions, respectively. We determined one-step interconversion as unfavourable under physiological conditions due to a 35 kcal mol(-1) activation energy barrier. All data were compared with analogue ones for fluvastatin (FLV) reported earlier and indicated that ATV is more flexible than FLV, not only due to the fact that it has more rotatable carbon-carbon single bonds, but also because ATV lactonistation-hydrolysis energy barriers are lower.

(−)‐R‐Mevalonolactone Studied by ROA and SERS Spectroscopy

“…Comparing the SERS and Raman spectra of (À)-Rmevalactone, the assignment of the bands in the SERS spectrum seems rather equivocal because all the signals are shifted, even about 50 cm -1 (but the calculations were not scaled). In the SERS spectrum, there are two strong bands, [26], ν C4C14 [21], ρ 1(CH3) [17], ρ 2(CH3) [10] 980 960 972 ρ C14H15H16 [27], ρ 2(CH3) [13], β 1/R6 [12], ρ 1(CH3) [9] 997 977 990 ρ C17H18H19 [25], ρ 2(CH3) [13], In the normal coordinate analysis, a nonredundant set of 51 internal coordinates was defined (Table S3, Supporting Information). The vibrations have been designated as follows: the stretching vibrations -ν (19), the six-membered ring deformations (β 1-3/R6 -in plane, τ 1-3/R6 -out-of plane) (6), the C = O group deformations (ρ C3O7 -in plane, γ C3O7 -out-of plane) (2), the methyl group deformations (β 1(CH3) -symmetric bending or umbrella vibration, β 2-3(CH3) antisymmetric bending, ρ 1-2(CH3) -rocking vibrations) (5), the "-CH 2 -" group in the ring deformations (δ -scissoring, ρ -rocking, ω -wagging, τ -twisting) (4x4), O-H bending (β C4O5H10 ) (1), and two torsions τ C4C6 and τ C4O5 (2).…”

“…It was also found that the enantiomeric pairs of δ‐lactones differ in odor and threshold of perception . The whole class of δ‐lactones are statins, which are currently the top‐selling cholesterol‐lowering drugs in the world . Some of them, like simvastatin and lovastatin, are administered directly as δ‐lactone prodrugs, which upon conversion to their respective hydroxy acid serve as strong competitive inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMG‐CoA reductase) .…”

“…11 The whole class of δ-lactones are statins, which are currently the top-selling cholesterol-lowering drugs in the world. 12 Some of them, like simvastatin and lovastatin, are administered directly as δlactone prodrugs, which upon conversion to their respective hydroxy acid serve as strong competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). 13 It has been shown that at physiological pH the lactone and acid species of statins coexist in equilibrium in vivo and the lactone-hydroxy acid interconversion undergoes reversibility, usually at a pH-dependent rate.…”

Efeito do lúpus eritematoso sistêmico na atividade do transportador de influxo sinusoidal OATP1B1 avaliado com base na farmacocinética e farmacodinâmica da atorvastatina

“…Em amostras de plasma com pH acima de 6, a forma lactona fica instável e o equilíbrio favorece a hidrólise, abrindo a lactona e produzindo a forma hidroxiácido. Já a forma ácida, é suscetível sob condições mais ácidas à formação de lactona (Figura 1) (GOOSEN et al, 2007;HERMANN;CHRISTENSEN;REUBSAET, 2005;NOWOSIELSKI, 2008;XIA, 2000;MACWAN et al, 2011;TURNER et al, 2018). Cerca de 70% da atividade inibitória total da HMG-CoA redutase é explicada pelos metabólitos ativos da ATV (LENNERNÄS, 2003).…”

“…O tempo de ultrafiltração representa um fator limitante para a viabilidade da análise em função da interconversão das formas ácida para as respectivas formas lactona da ATV e metabólitos. A manutenção do pH da amostra na faixa de 4 a 5 e temperatura de 4°C, minimiza a interconversão da ATV entre as formas ácida e lactona(GOOSEN et al, 2007;HERMANN;CHRISTENSEN;REUBSAET, 2005;NOWOSIELSKI, 2008;XIA, 2000; MACWAN et al, 2011;TURNER et al, 2018). Considerando que o pH do ultrafiltrado de plasma varia entre 8 e 9, a adição de solução tampão fosfato de potássio dibásico pH 7,4 permite a redução do pH, embora ainda com valores acima do pH necessário para a estabilidade das formas ácida e lactona.…”