Pravastatin

Sample preparation Condition an immobilized antibody column (preparation details in paper) with 4 mL water, 4 mL MeOH water 80 20, and 4 mL PBS. Add 1 mL plasma to the column, let stand for 15 min, wash with two 4 mL portions of water, wash with 4 mL PBS, wash with two 4 mL portions of water, elute with 4 mL MeOH. Add 100 pL 100 ng/mL IS in water to the eluate, evaporate to drjmess, reconstitute with 100 pL DMF, add 100 pL 47.6 pg/mL triethylamine in dioxane (Caution Dioxane is a carcinogen ), add 100 pL 51.8 pL/mL diethyl phosphorocyanidate in dioxane, add 100 pL 100 pg/mL N-dansylethylenediamine (Molecular Probes, Inc., Eugene OR) in dioxane, stir for 10 s, let stand at room temperature for 10 min, inject a 10 pL ahquot onto column A and elute to waste with mobile phase A. After 7.5 min elute the contents of column A onto column B with mobile phase B. After 2.5 min remove column A from the circuit. Elute column B with mobile phase B and monitor the effluent from column B. 

Column A 150 x 4.6 Ultron 300-C4 (Shinwa Chemical Industries) B 150 X 6 Cosmosil 5C18-AR (Nacalai Tesque) 

Mobile phase A MeCN 10 mM pH 2.4 citric acid 30 70 B MeCN 5 mM pH 2.6 citric acid 50 50 

Dumousseaux, C. Muramatsu, S. Takasaki, W. Takahagi, H. Highly sensitive and specific determination of pravastatin sodium in plasma by high-performance liquid chromatography with laser-induced fluorescence detection after immobilized antibody extraction. J.Pharm.ScL, 1994, 83, 1630-1636 

Sample preparation Condition a 1 mL C2 Bond-Elut SPE cartridge with 2 mL water, 2 mL MeOH, and 2 mL water. 1 mL Plasma + 1 mL 100 mM pH 7.2 KH2PO4, add to the SPE cartridge, wash with 2 mL water, elute with 500 pL MeCN water 75 25. Evaporate the eluate to dryness under reduced pressure, reconstitute with 80 pL IS solution, cen- 

Guard column 20 mm long Supelguard LC-18 Column 50 x 4.6 3 (xm Supelcosil LC-18 

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The cholesterol-lowering agents called statins, such as simvastatin (Zocor) and pravastatin (Pravachol), are among the most widely prescribed drugs in the world. Identify the functional groups in both, and tell how the two substances differ. 

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

Lovastatin is taken once daily, preferably with the evening meal. Fluvastatin, pravastatin, and simvastatin are taken, witiiout regard to meals, once daily in die evening or at bedtime... 

If fluvastatin or pravastatin is prescribed with a bile acid sequestrant, take fluvastatin 2 hours after die bile acid sequestrant and pravastatin at least 4 hours afterward. 

Hatanaka T. Clinical pharmacokinetics of pravastatin mechanisms of pharmacokinetic events. Clin Pharmacokinet 2000 Dec 39(6) 397-412. Review. 

Dinnett EM, Mungall MMB, Kent JA, Ronald ES, Gaw A. Closing out a large clinical trial lessons from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Clin Trials 2004 1.6 545-52. 

Figure 26-1. Biosynthesis of mevalonate. HMG-CoA reductase is inhibited by atorvastatin, pravastatin, and simvastatin. The open and solid circles indicate the fate of each of the carbons in the acetyl moiety ofacetyl-CoA.

Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage a phase II randomized placebo-controlled trial. Stroke 2005 36 1627-1632. 

Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques implications for plaque stabilization. Circulation 2001 103(7) 926-933. 

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

Over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol, specifically lowering LDL cholesterol with statins, is effective for both primary and secondary prevention of IHD-related events. Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvas-tatin.22,23 A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.23... 

Lovastati n 1 0, 20, 40 mg tablets 1 0 to 80 mg/day as a single dose (with evening meal) or divided twice daily with food Approximate equivalent doses of HMG-CoA reductase inhibitors are atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40 mg, pravastatin 40 mg, simvastatin 20 mg, and rosuvastatin 5 mg. 

With the exception of pravastatin which is mainly metabolized by isomerization in the gut to a relatively inactive metabolite, the other statins undergo biotransformation by the cytochrome P-450 system. Therefore, drugs known to inhibit statin metabolism should be used cautiously. The time until maximum effect on lipids for statins is generally 4 to 6 weeks. 

Hosobuchi, M., Kurosawa, K. and Yoshikawa, H. (1993) Application of computer on monitoring and control of fermentation process microbial conversion of ML-236B sodium to pravastatin. Biotechnology and Bioengineering, 42, 815-820. 

Pravastatin 4 Pravastatin Anti-cholesterol Hydroxylation Streptomyces carbophilus Single-stage fermentation [5]... 

Organic anion transporting OATP1/2 bromosulfophthalein (BSP), pravastatin,... 

Multidrug resistance MRP2 pravastatin, vinblastine, temocaprilat,... 

Nakai, D., et al. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J. Pharmacol. Exp. Ther. 2001, 297, 861-867. 

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