Cost-effectiveness of initial therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to treat hypercholesterolemia in a primary care setting of a managed-care organization.

From January 1994 through May 1995, Prudential HealthCare-North Texas prospectively studied 299 member patients diagnosed with hypercholesterolemia for whom pharmacotherapy with one of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also known as statins, was prescribed. The purpose of this study was to measure the relative cost-effectiveness (CE) of these drugs in a real-world setting. This study provides information to assist decision makers in managed-care organizations (MCO) in making formulary selections. The study used a prospective, randomized, balanced cohort design, examining patients who had been prescribed initial therapy with a statin drug as monotherapy. Costs (direct medical and indirect costs) and effectiveness (percent reduction in low-density lipoprotein cholesterol levels) were based on approximately the first 6 months of initial therapy. Both the MCO and patient perspectives were considered. In the base case, mean CE ratios were significantly lower for fluvastatin compared with lovastatin, pravastatin, and simvastatin from both the managed-care perspective and the patient perspective. Sensitivity analysis did not alter the CE conclusions, even under conditions of varying cost structures. Although differences were found in the effectiveness of lovastatin, pravastatin, and simvastatin measured in this study versus efficacy measured for these drugs in controlled clinical trials, sensitivity analysis suggests that these differences alone do not determine the superior CE of fluvastatin. Finally, this study supports the idea that well-designed formularies should consider drug CE (based on safety, effectiveness, and cost) and that integration of the pharmacy benefit management with other medical management is essential. These results provide evidence that fluvastatin may represent a more cost-effective formulary choice among statin products used for initial monotherapy of hypercholesterolemia.

Metabolism of azoxy derivatives of procarbazine by aldehyde dehydrogenase and xanthine oxidase.

Procarbazine, a 1,2-disubstituted hydrazine, is employed therapeutically in the treatment of Hodgkin's disease and a limited number of other neoplasias. The isomeric azoxy metabolites of procarbazine have recently been identified as the precursors of species responsible for both the anti-cancer efficacy and toxic effects mediated by this drug. This study demonstrates that cytosolic enzymes are involved in the metabolism of the azoxy metabolites of procarbazine. Two azoxy procarbazine oxidase activities were resolved by diethylaminoethyl (DEAE)-cellulose chromatography. The activity which did not bind to this column was purified to homogeneity and was identified as a phenobarbital-inducible form of cytosolic aldehyde dehydrogenase. This protein fraction was shown to metabolize only the azoxy 2 procarbazine isomer to yield N-isopropy-p-formylbenzamide (ALD) in a reaction which did not require NAD+ as cofactor. The ALD product formed was also a substrate for a subsequent NAD(+)-dependent reduction reaction catalyzed by that purified protein. The azoxy 2 procarbazine isomer and ALD were shown to be potent inhibitors of both the dehydrogenase and esterase activities of aldehyde dehydrogenase. The second azoxy procarbazine oxidase activity which was retained by the DEAE-cellulose column co-eluted with xanthine oxidase activity. Both the xanthine dehydrogenase/oxidase and azoxy procarbazine oxidase activities of this protein fraction were inhibited by allopurinol, a specific inhibitor of xanthine dehydrogenase. Xanthine dehydrogenase/oxidase was partially purified by an alternative procedure and was shown to metabolize both the azoxy 2 procarbazine isomer and ALD, ultimately producing N-isopropylterephthalamic acid. The ability of xanthine oxidase to metabolize azoxy 2 procarbazine and ALD was confirmed using commercial, purified milk xanthine oxidase.

Disposition of the monoclonal antibody-vinca alkaloid conjugate, KS1/4-DAVLB (LY256787), in Fischer 344 rats and rhesus monkeys.

The conjugate, KS1/4-DAVLB, of the murine monoclonal antibody KS1/4 with the vinca alkaloid 4-desacetylvinblastine (DAVLB) was administered intravenously to rats and monkeys. Terminal plasma half-life (t1/2) values were measured as radioequivalents and as functionally immunoreactive antibody conjugate after dosing with KS1/4-[3H]DAVLB. The t1/2 values, determined radiometrically, were 145 hr and 62 hr in male rats after 10 and 100 mg/kg doses and 92 hr and 90 hr in male and female monkeys after a 40 mg/kg dose. Comparable results were obtained when the functionally immunoreactive conjugate concentrations were determined by an enzyme-linked immunosorbent assay technique. The ratio of 35S:3H in the plasma after dosing rats with 100 mg/kg [35S]KS 1/4-[3H]DAVLB remained reasonably constant during 336 hr. Less than 1% of the total vinca alkaloid equivalents present in the plasma at any time could be extracted as free vinca species; the major vinca alkaloid metabolities present at early time points were hemisuccinate derivatives of DAVLB, whereas, at later times, DAVLB and its N-oxide were equally as concentrated. The major pathway of elimination was fecal with about one-half of the administered radioactivity cleared in 150-250 hr. After dosing with [35S]KS 1/4-[3H]DAVLB, the ratio of 35S:3H radioactivity in the bile was substantially less than that in the plasma. Evaluation of radioactivity eluted from the bile by size-exclusion HPLC showed that almost all of the tritium was associated with material of lower molecular weight than that of KS 1/4-DAVLB.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of the monoclonal antibody-vinca alkaloid conjugate KS1/4-DAVLB (LY256787) and free 4-desacetylvinblastine in tumor-bearing nude mice.

The monoclonal antibody-vinca alkaloid conjugate, KS1/4-DAVLB (LY256787), and free 4-desacetylvinblastine (DAVLB) were administered i.v. to male athymic nude mice bearing P3/UCLA human lung adenocarcinoma tumors. Although the plasma pharmacokinetics were similar between LY256787 and DAVLB (terminal plasma half-lives of 62 and 83 hr, respectively), substantial differences in the volumes of distribution and initial redistribution-elimination phases were found. Uptake of LY256787 into tumor was apparent, with maximal radioequivalent concentrations measured 96 hr after dosing; no similar uptake was found after dosing with free DAVLB. The ratios of concentrations of drug radioequivalents in tumor to those in other tissues were generally greater than 1.0 when measured 24 to 48 hr after dosing with LY256787 but were less than 1.0 after free DAVLB. These data support the concept of site-specific delivery to the tumor tissue of the vinca alkaloid by the antibody. Plasma pharmacokinetics and tissue distribution were compared in males and females with a lower dose of LY256787. No sex-related differences in the plasma pharmacokinetics were found (terminal half-lives of 90 and 84 hr in males and females). Some sex-related biodistribution differences occurred. In all studies, the primary route of elimination was fecal. These studies suggest that the KS1/4 monoclonal antibody targets DAVLB to the P3/UCLA human lung adenocarcinoma in vivo in the human xenograft model and that an increased therapeutic index may be achieved with LY256787 over conventional free drug therapy.

Novel glutathione conjugates formed from epoxyeicosatrienoic acids (EETs).

The catalysis of glutathione (GSH) conjugation to epoxyeicosatrienoic acids (EETs) by various purified isozymes of glutathione S-transferase was studied. A GSH conjugate of 14,15-EET was isolated by HPLC and TLC; this metabolite contained one molecule of EET and one molecule of GSH. Fast atom bombardment mass spectrometry of the isolated metabolite confirmed the structure as a GSH conjugate of 14,15-EET. Studies designed to determine the isozyme specificity of this reaction demonstrated that two isozymes, 3-3, and 5-5, efficiently catalyzed this conjugation reaction. The Km values for 14,15-EET were approximately 10 microM and the Vmax values ranged from 25 to 60 nmol conjugate formed min-1 mg-1 purified transferase 3-3 and 5-5. The 5,6-, 8,9-, and 11,12-EETs were also substrates for the reaction, albeit at lower rates. These results demonstrate that the EETs can serve as substrates for the cytosolic glutathione S-transferases.

Effect of cytosolic components on the metabolism of the hydrazide iproniazid.

The effects of thiols, such as glutathione (GSH), and the cytosolic glutathione S-transferases on the microsomal metabolism of the hydrazide iproniazid to hydrocarbon products were investigated. Thiol compounds stimulated propane production and depressed propylene production. Addition of preparations of cytosolic proteins to the microsomal reaction mixtures in the presence of GSH depressed production of propane by more than 80% and propylene by 50% compared to the GSH-mediated reaction. The purified glutathione S-transferases A and B were most potent in eliciting this effect; isozymes AA, C, and E had little or no effect on hydrocarbon production. Further, a mixture of these purified isozymes in the concentrations known to exist in cytosol affected hydrocarbon production in a manner similar to cytosol. Experiments performed with isolated hepatocytes and an inhibitor of these cytosolic enzymes further supported the involvement of these enzymes in altered hydrocarbon production. These isozymes were subsequently shown to catalyze the formation of a GSH conjugate, S-(2-propyl)glutathione. The decreases in hydrocarbon production by microsomes in the presence of the glutathione S-transferases and GSH were accompanied by production of slightly larger amounts of conjugate. These data indicate that the cytosolic glutathione S-transferases interact with an oxidative microsomal metabolite of iproniazid to enzymatically produce an S-(2-propyl)glutathione conjugate and thus prevent formation of a reactive species which would otherwise chemically decompose to yield hydrocarbons or to covalently bind to cellular macromolecules.

Aging selectively alters glutathione S-transferase isozyme concentrations in liver and lung cytosol.

The effects of aging on hepatic and pulmonary cytosolic glutathione S-transferase activities and concentrations were investigated in male Fischer 344 rats 3, 12, and 24 months old. Column isoelectric focusing of liver cytosol indicated that activities, measured with six epoxide substrates, of isozymes E, C, and B increased from 3 to 12 months of age and decreased from 3 to 24 months of age whereas activities of isozyme A were increased in the old group. With lung cytosol, activities of isozymes E, C, and B were decreased whereas isozyme A activities were increased in the old group. Purification to homogeneity of individual isozymes from liver and lung cytosol from each age group indicated that catalytic properties of isozymes were not altered by aging. Immunotitrations of hepatic and pulmonary cytosol from each age group showed that changes in the concentrations of these isozymes occurred with aging: heptic isozymes E, C, and B increased from 3 to 12 months of age and then decreased by 24 months of age, whereas isozymes A and AA were increased by 24 months of age. Pulmonary isozymes E, C, and B followed a pattern of decline from 3 to 24 months of age, whereas isozyme A concentrations were unchanged with increasing age. Analysis of these changes suggested that subunits Ya and Yc as one group and Yb and Y'b as another followed similar increases (from 3 to 12 months) and decreases (from 12 to 24 months) in the liver and that these subunits showed consistent decreases with age in the lung.

Effects of aging on hepatic and pulmonary glutathione S-transferase activities in male and female Fischer 344 rats.

The effects of aging on cytosolic glutathione S-transferase activities were evaluated with liver and lung cytosol from male and female Fischer 344 rats 3, 12, and 24 months of age. Age-related changes were tissue-, sex-, and substrate-specific. With liver and lung cytosol from both males and females, rates of metabolism of 1,2-epoxy-3-(p-nitrophenoxy)propane and p-nitrobenzyl chloride were lower in the old group than in the young group; however, patterns of decrease differed with tissue and sex. With 1,2-dichloro-4-nitrobenzene, metabolism was affected by aging only in liver and lung cytosol from males. Finally, with 1-chloro-2,4-dinitrobenzene, metabolic rates were altered during aging only with liver cytosol from females. However, the apparent Km was higher with liver cytosol from old males; those values from lung cytosol of males and liver or lung cytosol from females were unchanged. These data indicate that changes in the cytosolic glutathione S-transferase isozymes occurred during aging.

Hepatic and pulmonary cytosolic metabolism of epoxides effects of aging on conjugation with glutathione.

In liver cytosol from male Fischer 344 rats, glutathione S-transferase specific activities with six epoxide substrates were lower in the 24-month-old (senescent) group than in the 3-month-old (young) group. With lung cytosol from males and liver and lung cytosol from females, specific activities declined with only some of the substrates. Age-related increases in protein content in male and female rat liver occurred by 12 months of age (middle-age) and remained elevated through senescence. In addition, increases in liver weights in males similarly occurred so that total metabolic rates tended to be highest in middle-aged males and similar in young and senescent groups. Few changes similar to these were found in liver cytosol from females or lung cytosol from males or females. Thus, tissue-, sex-, and substrate-specific alterations in epoxide metabolism occurred during aging.