Mevinolinic acid

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a Ki of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reductase reaction (see figure). 

The structures of (inactive) lovastatin, (active) mevinolinic acid, mevalonate, and synvinolin. 

Prasad and Sirkar (1990) have worked with actual streams obtained from Merck. Their work includes the recovery of mevinolinic acid, obtained by fermentation, which is a precursor to the hypocholestcrmic agent Mevinolin. 

Todd, R.S., Reeve, M., and Davidson, A.H., Preparation of phosphorus containing alkynyl derivatives useful as intermediates in the preparation of keto phosphonates and mevinolinic acid derivatives, British Bio-Technology, Int. Patent Appl. WO 9322321, 1992 Chem. Abstr, 120, 245504, 1994. 

Monacolins J (7), L (8), M (9) and X (10), dihydromonacolin L (11) and 3a-hydroxy-3,5-dihydromonacolin L acid (12) were isolated from cultures of M. ruber [31-34]. Mevinolinic acid (13) and dihydromevinolin (14) were produced by A. terreus [27,35]. Of them, HMG-CoA reductase inhibitory activities of dihydrocompactin and dihydromevinolin were comparable to those of mevastatin and lovastatin [36]. 

Fig. (6). Mevinolinic acid and dihydromevinolin isolated from Aspergillus terreus...

Sample preparation Prepare a 1 mL Bond-Elut C2 SPE cartridge by washing with 1 mL MeOH and 1 mL buffer. Plasma. 500 xL Plasma -i- 500 p,L buffer, keep in an ice water mixture, add 100 p,L MeCN water 60 40, add 50 pL 5 pg/mL methyl mevinolinic acid in MeCN water 60 40, mix, add to the SPE cartridge, wash twice with 1 mL huffer, wash twice with 1 mL MeCN buffer 20 80, elute with 400 pL MeCN water 75 25, inject a 30 pL ahquot of eluant. Bile. Inject a 10 pL aliquot directly. (Buffer was 100 mM pH 7.2 potassium phosphate buffer.)... 

Stubbs, R.J. Schwartz, M. Bayne, W.F. Determination of mevinolin and mevinolinic acid in plasma and bile by reversed-phase high-performance liquid chromatography. J.Chromatogr., 1986,383, 438-443... 

Another example of quantification with the LC-MS/MS combination is the determination of mevinolinic acid, which is a major metabolite of lavastatin in human blood [12]. Clinical trials have shown that lavastatin lowers the serum level of cholesterol by acting as a potent inhibitor of 3-hydroxy-3-methylglutoryl-coenzyme A. Mevinolinic acid is the active form of lavastatin in this functional role. In this method, methyhnevinolinic acid was used as an IS. CID of the [M—H] ions of the analyte and methylmevinolinic acid produces a common fragment ion at m/z 319. The negative-ion MRM acquisition mode was used to monitor the precursor-product reactions of the analyte and internal standard. With this method, quantification of mevinolinic acid can be performed at the 50-pg/mL level. 

Lovastatin is rapidly metabolised, which is undesirable for any dmg likely to be chronically administered. In order to achieve once-daily dosing, steric hindrance around the ester carbonyl was increased by the introduction of an extra methyl group close to the ester bond in order to reduce the rate of esterase hydrolysis. This resulted in formation of simvastatin, a highly successful lipid-lowering agent. Simvastatin (like lovastatin) is inactive until metabolised in the liver to form its active metabolite mevinolinic acid (Fig. 8.48). Part of mevino-linic acid is stmcturally similar to the HMG portion of HMG-GoA, the substrate for HMG-CoA reductase, and hence competes with it for the active site of the enzyme. This reduces the amount of mevalonic acid which is produced. Mevalonic acid is a precursor of cholesterol. 

Figure 8.48 Structural similarity between mevinolinic acid and FlMG-CoA.

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