Lovastatin Acid Research Articles

Comparison of 3‐Hydroxy‐3‐methylglutaryl Coenzyme A (HMG‐CoA) Reductase Inhibitors (Statins) as Inhibitors of Cytochrome P450 2C8

Statins are involved in different types of drug interactions. Our objective was to study the effect of statins on cytochrome P450 (CYP) 2C8-mediated paclitaxel 6 alpha-hydroxylation by incubating paclitaxel and statins (0--100 microM) with pooled human liver microsomes. Simvastatin, lovastatin, atorvastatin and fluvastatin were the most potent inhibitors of CYP2C8 activity with K(i) (IC(50)) values of 7.1 (9.6) muM, 8.4 (15) microM, 16 (38) microM and 19 (37) microM, respectively. Cerivastatin, simvastatin acid and lovastatin acid were less potent inhibitors with K(i) (IC(50)) values ranging from 32 to 55 (30--67) microM. Rosuvastatin and pravastatin showed no appreciable effect on CYP2C8 activity even at 100 microM. In conclusion, all the statins tested, except rosuvastatin and pravastatin, had a significant inhibitory effect on the activity of CYP2C8 in vitro. Because many of the statins accumulate in the liver and because also their metabolites may inhibit CYP2C8 activity, in vivo studies are needed to investigate a possible interaction of simvastatin, lovastatin, atorvastatin and fluvastatin with CYP2C8 substrate drugs.

DIFFERENTIAL INTERACTION OF 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE INHIBITORS WITH ABCB1, ABCC2, AND OATP1B1

The present study examined the interaction of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (atorvastatin, lovastatin, and simvastatin in acid and lactone forms, and pravastatin in acid form only) with multidrug resistance gene 1 (MDR1, ABCB1) P-glycoprotein, multidrug resistance-associated protein 2 (MRP2, ABCC2), and organic anion-transporting polypeptide 1B1 (OATP1B1, SLCO21A6). P-glycoprotein substrate assays were performed using Madin-Darby canine kidney (MDCK) cells expressing MDR1, and the efflux ratios [the ratio of the ratio of basolateral-to-apical apparent permeability and apical-to-basolateral permeability between MDR1 and MDCK] were 1.87, 2.32/4.46, 2.17/3.17, and 0.93/2.00 for pravastatin, atorvastatin (lactone/acid), lovastatin (lactone/acid), and simvastatin (lactone/acid), respectively, indicating that these compounds are weak or moderate substrates of P-glycoprotein. In the inhibition assays (MDR1, MRP2, Mrp2, and OATP1B1), the IC50 values for efflux transporters (MDR1, MRP2, and Mrp2) were >100 microM for all statins in acid form except lovastatin acid (>33 microM), and the IC50 values were up to 10-fold lower for the corresponding lactone forms. In contrast, the IC50 values for the uptake transporter OATP1B1 were 3- to 7-fold lower for statins in the acid form compared with the corresponding lactone form. These data demonstrate that lactone and acid forms of statins exhibit differential substrate and inhibitor activities toward efflux and uptake transporters. The interconversion between the lactone and acid forms of most statins exists in the body and will potentially influence drug-transporter interactions, and may ultimately contribute to the differences in pharmacokinetic profiles observed between statins.

The effect of CYP2D6 genotype on the pharmacokinetics of lovastatin in Chinese subjects

To investigate whether specific CYP2D6 genotype can influence the pharmacokinetics of lovastatin, a drug with multi-metabolic pathway (CYP3A4, 2C9, 2D6 and hydrolysis). A single 40 mg oral dose of lovastatin was administered to 19 healthy subjects. Multiple blood samples were collected over 24 h, and plasma concentrations of lovastatin and lovastatin acid (one of the major metabolites by hydrolysis) were determined by an LC-MS-MS method. CYP2D6 genotype was determined using PCR followed by restriction enzyme analysis or allele-specific PCR tests. The subject distribution were: 4 homozygous CYP2D6*1 (*1/*1), 7 heterozygous CYP2D6*10 (*1/*10 or *2/*10) and 8 homozygous CYP2D6*10 (*10/*10) carriers. The area under the plasma concentration-time curve (AUC0–24) and terminal elimination half-life (t1/2) of lovastatin among the three groups were 12.4+4.0, 20.2+10.4 and 30.0+10.5 ng·h/ml, and 4.4+0.9, 6.0+2.4 and 8.1+2.5 h respectively (one-way ANOVA, p=0.022 for AUC0-24 and p=0.046 for t1/2). In comparison to the homozygous CYP2D6*1 carriers, the oral clearance of lovastatin were lower by 32.5% (p<0.05) and 55.2% (p<0.01) in the heterozygous CYP2D6*10 and homozygous CYP2D6*10 carriers respectively. The AUC0-24 of lovastatin acid also tended to be higher in the heterozygous CYP2D6*10 and homozygous CYP2D6*10 carriers; however, the difference was not statistically significant. These preliminary results in Chinese subjects show that among extensive metabolizers of CYP2D6, the pharmacokinetics of lovastatin appears to be dependent on CYP2D6 genotype. Clinical Pharmacology & Therapeutics (2004) 75, P18–P18; doi: 10.1016/j.clpt.2003.11.067

Transport mechanism for lovastatin acid in bovine kidney NBL-1 cells: kinetic evidences imply involvement of monocarboxylate transporter 4

We previously indicated that lovastatin acid, a 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was transported by a monocarboxylate transporter (MCT) in cultured rat mesangial cells. In this study, to identify the MCT isoform(s) responsible for the lovastatin acid uptake, the transport mechanism was investigated using bovine kidney NBL-1 cells, which have been reported to express only MCT4 at the protein level. On RT-PCR analysis, the message of mRNAs for MCT1 and MCT4 was detected in the NBL-1 cells used in this study, which was confirmed by kinetic analysis of [ 14 C ] l-lactic acid uptake, consisting of high- and low-affinity components corresponding to MCT1 and MCT4, respectively. The lovastatin acid uptake depended on an inwardly directed H +-gradient, and was inhibited by representative monocarboxylates, but not by inhibitors/substrates for organic anion transporting polypeptides and organic anion transporters. In addition, l-lactic acid competitively inhibited the uptake of lovastatin acid and lovastatin acid inhibited the low affinity component of [ 14 C ] l-lactic acid uptake dose dependently. The inhibition constant of l-lactic acid for lovastatin acid uptake was almost the same as the Michaelis constant for [ 14 C ] l-lactic acid uptake by the low-affinity component. These kinetic evidences imply that lovastatin acid was taken up into NBL-1 cells via MCT4.

Monocarboxylate Transporter Mediates Uptake of Lovastatin Acid in Rat Cultured Mesangial Cells

To clarify the uptake mechanism(s) for statins, we examined whether monocarboxylate transporter (MCT) contributed to the uptake of lovastatin acid by rat cultured mesangial cells. Expression of mRNAs for MCT1, 2, and 4 was confirmed in mesangial cells. The uptake of lovastatin acid by mesangial cells increased with decreasing extracellular pH. There was clear overshooting in lovastatin acid uptake by the ATP-depleted cells in the presence, but not in the absence, of an inwardly directed H(+)-gradient. The representative MCT substrates/inhibitors inhibited the lovastatin acid uptake. In particular, the inhibition of lovastatin acid uptake by L-lactic acid at the concentration of 80 mM reached 70%, and L-lactic acid and valproic acid inhibited the uptake competitively. On preloading of mesangial cells with L-lactic acid or valproic acid, the lovastatin acid uptake was significantly stimulated. The inhibition constant of L-lactic acid for the lovastatin acid uptake was 32 mM, and this value is comparable to the Michaelis constant (>20 mM) of L-lactic acid for MCT4 described elsewhere. These results demonstrate that lovastatin acid was largely taken up by mesangial cells via MCT, and suggest that MCT4 might contribute to lovastatin acid uptake in the cells.

Advicor (niacin extended-release and lovastatin tablets).

Advicor (niacin extended-release and lovastatin) is a newly Food and Drug Administration-approved combination medication used in addition to adjunctive treatment of primary hypercholesterolemia and mixed dyslipidemia. The drug is a combination of two familiar medications used to treat patients with elevated low-density lipoprotein (LDL) cholesterol and total cholesterol, low high-density lipoprotein (HDL) cholesterol, and elevated triglycerides. It combines extended-release niacin and lovastatin. Niacin reduces LDL cholesterol, apolipoprotein B, lipoprotein(a), triglycerides, and total cholesterol. It also increases HDL cholesterol. Lovastatin reduces both normal and elevated LDL cholesterol. Apolipoprotein B also falls with treatment. The mechanism of action of niacin is not thoroughly understood. Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that prevents the production of cholesterol. Lovastatin is a prodrug and needs to be hydrolyzed to its active metabolite, lovastatin acid. The mechanism of action of LDL reduction involves the reduction of very LDL cholesterol and induction of the LDL receptor, which leads to reduction of the production or increased catabolism of LDL cholesterol. Following a single dose of the drug, peak plasma niacin and lovastatin levels were obtained in 5 hours and 2 hours, respectively. The extent of absorption of niacin was increased with food. Lovastatin is incompletely absorbed and has considerable interindividual variability. Grapefruit juice increases the absorption by at least 30%. Niacin undergoes first-pass metabolism and is excreted in the urine. Niacin concentrations are higher in women than in men. Lovastatin also undergoes first-pass metabolism by the cytochrome P450 3A4 system and is excreted in the urine and bile. The drug can cause significant liver dysfunction; therefore, careful monitoring of hepatic function must be performed. The drug should not be substituted for equivalent doses of immediate-release niacin. The drug should be used very cautiously in patients with substantial alcohol consumption or a history of liver disease. Liver function tests should be performed on all patients at the beginning of therapy and every 6–12 weeks for at least 6 months, then periodically. The drug should be stopped if liver function values are three times the upper limits of normal. Rhabdomyolysis has been reported in patients with and without renal insufficiency. Periodic creatine phosphokinase determinations may be considered in patients suspected of developing rhabdomyolysis. The drug should be stopped if rhabdomyolysis is suspected. The use of the drug with cyclosporine or fibrates should be avoided. The drug should be stopped before giving azole antifungal agents and macrolides. Aspirin may decrease the metabolic clearance of niacin. Niacin may potentiate the effects of ganglionic blocking drugs, causing postural hypotension. The most common adverse reaction is flushing (53%–83%). The incidence of flushing can be reduced by pretreatment with aspirin or another nonsteroidal anti-inflammatory drug 1/2 hour prior to taking the drug. Other adverse reactions include infection (20%), headache (9%), nausea (7%), and pruritus (7%). The usual starting dose is 500 mg niacin extended-release and 20 mg lovastatin. The drug should be taken at bedtime with a low-fat snack. The tablet should not be broken, crushed, or split. Dosing can be increased at 4-week intervals until the desired result is achieved. The maximal dosage of the drug is 1000 mg niacin extended-release and 20 mg lovastatin. Advicor is a new combination drug consisting of niacin extended-release and lovastatin. It should be used to adjunctively treat patients with primary hypercholesterolemia and mixed dyslipidemia.

A multiple-dose pharmacodynamic, safety, and pharmacokinetic comparison of extended- and immediate-release formulations of lovastatin

Background: Because lovastatin is efficiently extracted by the liver and because its administration in divided doses is associated with increased efficacy, an extended-release (ER) formulation may have the potential for a dose-sparing advantage relative to the immediate-release (IR) formulation in the treatment of hypercholesterolemia. Objective: This study compared the short-term pharmacodynamics, safety, and pharmacokinetics of multiple doses of lovastatin ER with those of lovastatin IR in patients with fasting low-density lipoprotein cholesterol (LDL-C) levels between 130 and 250 mg/dL and fasting triglyceride levels <350 mg/dL. Methods: The study had a randomized, single-blind, positive-controlled, 2-way crossover design, with a 4-week diet/placebo run-in period and two 4-week active-treatment periods. During period 1, patients received either lovastatin ER or lovastatin IR (both 40 mg OD). After 4 weeks of the initial study treatment and a 2-week washout period, patients were switched to the alternate treatment (period 2). Pharmacodynamic parameters (LDL-C, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels) were evaluated by combining data from weeks 3 and 4 of treatment. In a pharmacokinetic substudy, maximum plasma concentrations (C max) and area under the plasma concentration—time curve from zero to 24 hours (AUC 0–24) were determined for lovastatin, lovastatin acid, and total and active inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on days 1 and 28 of active treatment. The geometric mean ratio of AUC 0–24 (lovastatin ER/lovastatin IR) was also calculated for each of these substances. Results: Of 76 patients who entered the run-in period, 26 (12 men, 14 women; mean age, 56.2 years) were randomized to receive active treatment and 24 were included in the efficacy analysis; 13 patients were included in the pharmacokinetic substudy, 12 of whom had complete pharmacokinetic data. Compared with lovastatin IR, lovastatin ER produced a 3.9% greater reduction in LDL-C ( P = 0.044). Changes in other lipid parameters were not statistically significant. In the pharmacokinetic substudy, C max values for lovastatin, lovastatin acid, and inhibitors of HMG-CoA reductase were lower at day 28 with lovastatin ER than with lovastatin IR. The AUC 0–24 ratio for lovastatin was 1.91 (90% CI, 1.77–3.35), reflecting higher bioavailability of the pro-drug with lovastatin ER; in contrast, the ratios for lovastatin acid and active and total inhibitors of HMG-CoA reductase were <1. Conclusions: In this short-term study in a small number of patients, lovastatin ER 40 mg produced significantly greater LDL-C lowering than did an equal dose of lovastatin IR, with a relatively low C max and comparable systemic exposure to lovastatin acid and active and total inhibitors of HMG-CoA reductase. Lovastatin ER was well tolerated, with no discontinuations due to adverse events.

Pharmacological concentrations of the HMG-COA reductase inhibitor lovastatin decrease the formation of the Alzheimer b-amyloid peptide in vitro and in patients

Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the beta-amyloid peptide (Abeta) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Abeta formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Abeta formed. This effect was observed at concentrations of 0.05-5 microM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Abeta in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized study with 10-60-mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum Abeta concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Abeta concentrations showed a significant (p < 0.0348), dose-dependent decrease. Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p< 0.05). Our results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that lovastatin reduces Abeta formation and may thereby be effective in delaying the onset and/or slowing the progression of AD.

Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide.

Epidemiological studies have demonstrated that hypercholsterolemia is a significant risk factor for Alzheimer's disease (AD). The mechanism by which increased cholesterol may contribute to AD is unknown. However, as the generation and accumulation of the amyloid Abeta peptide in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels can regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells in the presence of lipid depleted serum, with or without the active metabolite of the HMG-CoA reductase inhibitor lovastatin. After confirming that cholesterol was depleted in the cells, we then measured the fraction of Abeta formed from its precursor betaPP under each condition. We observed that cholesterol depletion led to a profound decrease in the levels of Abeta released from the cells. This effect of lovastatin acid was observed at concentrations of 0.05-5 &mgr;M, ranges where this compound is effective at inhibiting HMG-CoA reductase, thereby inhibiting cholesterol synthesis. In contrast, the release of an additional AbetaPP fragment, AbetaPPs, was only modestly reduced by cholesterol treatment. In further studies, we determined that the decreased release of Abeta was not due to its accumulation in the cell, but rather due to decreased formation of Abeta. Finally, we were able to exclude decreased maturation (glycosylation and sulfation) of newly synthesized AbetaPP as a cause for the effects of lovastatin acid on betaPP processing and Abeta formation. Our results demonstrate that reducing cellular cholesterol by the use of an HMG-CoA reductase inhibitor regulates Abeta formation. This effect may involve alterations in the trafficking of AbetaPP and/or alterations in the activity of the proteases that cleave AbetaPP. The results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that reduction in cholesterol may delay the onset and/or slow the progression of AD.

HMG-CoA reductase inhibitors and P-glycoprotein modulation.

1. Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein 1a/b (mdr1a/1b). 2. P-gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively. 3. Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P-gp and results were comparable for both methods. 4. In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P-gp affinity in drug screening that is especially useful for early phases of drug development.

Inhibitory Effect of Statins on Fetal Bovine Serum‐Induced Proliferation of Rat Cultured Mesangial Cells and Correlation Between Their Inhibitory Effect and Transport Characteristics

Mesangial cells play an important role in physiologic functions, including the regulation of glomerular filtration, and as a pathogenic factor for proliferative glomerulonephritis. We compared the potencies of the inhibitory effects of simvastatin acid, lovastatin acid, and pravastatin on fetal bovine serum (FBS)‐induced proliferation of rat cultured mesangial cells, and examined the correlation between their inhibitory effects and intracellular concentrations. We also investigated the transport of the statins in the cells, and whether or not their intracellular concentrations were determined by their transport characteristics. It appeared that the growth inhibitory effects on FBS‐induced proliferation of mesangial cells of simvastatin acid and lovastatin acid were approximately the same, but that of pravastatin was extremely weak compared with the others. The growth inhibitory effects of these agents were suggested to depend, at least in part, on the amount incorporated intracellularly. Simvastatin acid, lovastatin acid, and pravastatin appeared to be taken up by mesangial cells via a common carrier, the uptake capacity being determined by their lipophilicity. Therefore, it was thought that the growth inhibitory effects of the statins partially depended on their carrier‐mediated uptake by mesangial cells. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1594–1604, 2000

Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid

Lovastatin is a cholesterol-lowering drug that can cause myopathy as a rare side effect. Concomitant use of certain drugs (e.g., cyclosporine) increases the risk of skeletal muscle toxicity. Lovastatin is metabolized by CYP3A4. Because itraconazole is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between these drugs. In this double-blind, randomized, two-phase crossover study, 12 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were measured up to 24 hours. On average, itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration-time curve (AUC) more than twentyfold (p < 0.001). The mean Cmax of the active metabolite, lovastatin acid, was increased 13-fold (range, tenfold to 23-fold; p < 0.001) and the AUC(0-24) twentyfold (p < 0.001). In one subject plasma creatine kinase was increased tenfold within 24 hours of lovastatin administration during the itraconazole phase but not during the placebo phase. No increase in creatine kinase was observed in the other subjects. Itraconazole greatly increases plasma concentrations of lovastatin and lovastatin acid. Inhibition of CYP3A4-mediated metabolism probably explains the increased toxicity of lovastatin caused not only by itraconazole but also by cyclosporine, erythromycin, and other inhibitors of CYP3A4. Their concomitant use with lovastatin and simvastatin should be avoided, or the dose of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Relative benefits of lovastatin and nicotinic acid in hypercholesterolaemia

Relative benefits of lovastatin and nicotinic acid in hypercholesterolaemia

Lipoprotein Responses to Treatment with Lovastatin, Gemfibrozil and Nicotinic Acid in Normolipidemic Patients with Hypoalphalipoproteinemia

Background: The lipoprotein responses to conventional lipid-modifying drugs have not been adequately evaluated in normolipidemic patients with hypoalphalipoproteinemia (low levels of high-density lipoproteins). The purpose of this study was to compare responses to lovastatin, gemfibrozil, and nicotinic acid in such patients. Methods: The first phase of the study compared lipoprotein responses to lovastatin and gemfibrozil in 61 middle-aged men with low levels of high-density lipoproteins. In the second phase, 37 patients agreed to take nicotinic acid; 27 patients finished this phase at a dose of 4.5 g/d. Nicotinic acid results were compared with those with lovastatin and gemfibrozil in the same patients. Results: In the first phase, both drugs effectively lowered triglyceride levels. Gemfibrozil therapy increased high-density lipoprotein cholesterol levels by 10% and lovastatin by 6%, but lovastatin was much more effective for reducing low-density lipoprotein levels. Nicotinic acid did not significantly lower low-density lipoprotein levels in the second phase, but it raised high-density lipoprotein levels by 30%. Conclusions: Gemfibrozil therapy produced the least favorable response of the three drugs. Lovastatin markedly lowered low-density lipoprotein levels but only modestly raised levels of high-density lipoprotein, whereas nicotinic acid had the opposite effect. Consequently, the latter two drugs similarly reduced low-density lipoprotein— high-density lipoprotein ratios, although these effects were obtained in different ways. Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease. (Arch Intern Med. 1994;154:73-82)

Pharmacokinetic interaction between propranolol and the HMG‐CoA reductase inhibitors pravastatin and lovastatin.

1. Single oral 20 mg doses of the HMG-CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four-way crossover study. 2. Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3. Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration-time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4. Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5. These decreases in systemic drug concentrations may reflect enhanced drug first-pass hepatic clearance in the presence of propranolol. 6. The clinical significance of these changes is likely to be small.

Treating serum lipid abnormalities in high-priority patients

Normalization of serum lipid levels should be initiated as soon as possible in patients with myocardial, cerebrovascular, or peripheral vascular disease. Clinical trials indicate that coronary artery disease and overall mortality rates can be reduced and atherosclerosis stabilized or reversed by lipid-lowering therapy. Treatment should lower low-density lipoprotein cholesterol levels to 130 mg/dL or less and total triglyceride levels to 150 mg/dL or less and increase high-density lipoprotein cholesterol levels to at least 52 mg/dL in men and 66 mg/dL in women. Nonlipid coronary risk factors should be eliminated when possible. Lipid-lowering therapy may consist of dietary modification and drug treatment with colestipol hydrochloride (Colestid), cholestyramine (Cholybar, Questran), lovastatin (Mevacor), gemfibrozil (Lopid), and nicotinic acid (Nicolar).

Comparative Pharmacokinetics and Pharmacodynamics of Pravastatin and Lovastatin

The oral bioavailability of two HMG-CoA reductase inhibitors, pravastatin and lovastatin, was investigated in this randomized, two-way crossover study. Twenty healthy men were randomly assigned to treatment with a 40-mg dose of pravastatin or lovastatin once daily for 1 week; steady state kinetics were assessed after the last dose. After 1 week of washout, each subject received the alternate treatment. Serum specimens were assayed by gas chromatography/mass spectrometry (GC/MS) for intact pravastatin or lovastatin acid and by bioassay for active inhibitor concentration and, after hydrolysis of lactones, for total inhibitor concentration. The systemic bioavailabilities of total (active plus potentially active) inhibitors for the two drugs were different, with the mean AUC value for lovastatin being 50% higher than that of pravastatin (mean +/- SEM AUC0-24 values of 285 +/- 25 and 189 +/- 13 ng-equiv x hr/mL, respectively, P less than .0001). Pravastatin, which is administered as the monosodium salt, is present in the systemic circulation as the open acid; lovastatin, which is administered as the lactone, is present as both open-acid active metabolites (62%) and closed-ring lactone metabolites (38%), which are potentially active. Based on mean AUC values, pravastatin accounted for 75% of the active inhibitors from a pravastatin dose. Lovastatin acid accounted for just 25% of the active inhibitors from a lovastatin dose, with the remainder due to other active metabolites. Significant decreases from baseline in total and low-density lipoprotein (LDL) cholesterol were observed during the first treatment leg for both pravastatin and lovastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiology of the mesangial cell.

Ce travail resume et discute de nombreuses investigations realisees dans le but d'etudier la structure, la physiologie et le role des cellules mesengiales

Tissue-selective acute effects of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase on cholesterol biosynthesis in lens.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis, lower serum cholesterol by increasing the activity of low density lipoprotein (LDL) receptors in the liver. In rat liver slices, the dose-response curves for inhibition of [14C]acetate incorporation into cholesterol were similar for the active acid forms of lovastatin, simvastatin, and pravastatin. The calculated IC50 values were approximately 20-50 nM for all three drugs. Interest in possible extrahepatic effects of reductase inhibitors is based on recent findings that some inhibitors of HMG-CoA reductase, lovastatin and simvastatin, can cause cataracts in dogs at high doses. To evaluate the effects of these drugs on cholesterol synthesis in the lens, we developed a facile, reproducible ex vivo assay using lenses from weanling rats explanted to tissue culture medium. [14C]Acetate incorporation into cholesterol was proportional to time and to the number of lenses in the incubation and was completely eliminated by high concentrations of inhibitors of HMG-CoA reductase. At the same time, incorporation into free fatty acids was not inhibited. In marked contrast to the liver, the dose-response curve for pravastatin in lens was shifted two orders of magnitude to the right of the curves for lovastatin acid and simvastatin acid. The calculated IC50 values were 4.5 +/- 0.7 nM, 5.2 +/- 1.5 nM, and 469 +/- 42 nM for lovastatin acid, simvastatin acid, and pravastatin, respectively. Thus, while equally active in the liver, pravastatin was 100-fold less inhibitory in the lens compared to lovastatin and simvastatin. Similar selectivity was observed with rabbit lens. Following oral dosing, ex vivo inhibition of [14C]acetate incorporation into cholesterol in rat liver was similar for lovastatin and pravastatin, but cholesterol synthesis in lens was inhibited by lovastatin by as much as 70%. This inhibition was dose-dependent and no inhibition in lens was observed with pravastatin even at very high doses. This tissue-selective inhibition of sterol synthesis by pravastatin was likely due to the inability of pravastatin to enter the intact lens since pravastatin and lovastatin acid were equally effective inhibitors of HMG-CoA reductase enzyme activity in whole lens homogenates. We conclude that pravastatin is tissue-selective with respect to lens and liver in its ability to inhibit cholesterol synthesis.

Determination of lovastatin acid in serum by gas chromatography/mass spectrometry

The acid form of lovastatin, an HMG-CoA reductase inhibitor, was analyzed by gas chromatography/negative-ion chemical ionization mass spectrometry after derivatization with pentafluorobenzyl bromide and bis-(trimethylsilyl)trifluoroacetamide (BSTFA). Mass spectrometry of this derivative produced a dominant [M-181]- ion under chemical ionization conditions using ammonia as the reagent gas. The limit of detection was approximately 2 pg injected on column.