1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two‐period, crossover design in 12 in‐patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.
Ten healthy subjects received 10 mg oral enalapril (MK 421) daily for a period of 8 days. Renal clearances of electrolytes, urate and phosphate were monitored and factored for glomerular filtration rate, as measured by creatinine clearance, with particular emphasis on the first and eighth day of treatment. Apart from a fall of around 10% in creatinine clearance between 1‐2 h on both days 1 and 8, GFR remained unchanged throughout the study. Fractional sodium excretion increased in a biphasic manner by approximately 50% over control between 1‐2 h and 4‐8 h on day 1. Significant chloruresis (+39.0 +/‐ 12.9%) and kaluresis (+26.5 +/‐ 10.3%) occurred between 4‐8 h. Urinary pH increased between 0‐1 h (+0.29 +/‐ 0.12; P less than 0.05), and between 4‐8 h (+0.50 +/‐ 0.08; P less than 0.01). The biphasic saluretic effect was also seen between 1‐2 h and 4‐8 h on day 8. Enalapril caused significant increases in urate and phosphate excretion on day 8 of therapy. There was a biphasic increase in fractional urate excretion at 1‐2 h (+28.1 +/‐ 6.9%; P less than 0.05) and at 4‐8 h (+21.0 +/‐ 6.0% P less than 0.01). Significant phosphaturia (+36.8 +/‐ 5.2%; P less than 0.05) was also observed at 4‐8 h on day 8. Urinary drug excretion was also biphasic; over the first 2 h the predominant drug form was unchanged enalapril, whilst the peak excretion of the diacid metabolite, enalaprilat, occurred at 4‐8 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Using a randomized crossover design, 1-g intravenous doses of cephalothin and cefoxitin, a cephalosporinase-resistant cephamycin, were infused into 12 normal adult males over periods of 120, 30, and 3 min, the last with and without prior intravenous infusions of probenecid (1 g). Mean peak serum concentrations of antibiotic activity after cephalothin infusions were 23, 56, 103, and 102 μg/ml, respectively, and after cefoxitin infusions they were 27, 74, 115, and 125 μg/ml, respectively. Probenecid treatment prolonged the terminal serum half-life of cephalothin-like activity from 0.52 to 1.0 h, and of cefoxitin from 0.68 to 1.4 h. In contrast to cephalothin, which was found to be metabolized about 25% to the less active desacetyl form, cefoxitin was metabolized less than 2% to the virtually inactive descarbamyl form, as judged from urinary recoveries. Neither antibiotic displayed detectable organ toxicity. Of 300 recent clinical isolates of gram-negative bacilli other than Pseudomonas spp., 83% were susceptible to cephalothin but 95% were susceptible to cefoxitin. Organisms resistant to cephalothin but susceptible to cefoxitin included strains of Escherichia coli, Proteus vulgaris, Klebsiella spp., Serratia marcescens, Enterobacter spp., and Bacteroides spp.
1 The disposition of two angiotensin converting‐enzyme inhibitor drugs was studied in normal volunteers. One drug was enalapril maleate (MK‐ 421), which requires in vivo esterolysis to yield active inhibitor (MK‐ 422). The other was a lysine analogue of MK‐422 (MK‐521), which requires no bioactivation. 2 Absorption of enalapril maleate (10 mg, p.o.) was rapid, with peak serum concentrations of enalapril observed 0.5‐1.5 h after administration. Based upon urinary recovery of total drug (enalapril plus MK‐422), absorption was at least 61%. Bioactivation appeared to be largely post‐absorptive. From the ratio of MK‐422 to total drug in urine, the minimum extent of bioactivation was estimated at 0.7. 3 A similar dose of MK‐521 was absorbed more slowly, reaching peak serum concentrations 6‐8 h following drug administration. Minimum absorption, based upon urinary recovery, was 29%. 4 Serum concentration v time profiles for both drugs were polyphasic and exhibited prolonged terminal phases. 5 Recovery in urine and faeces of administered enalapril maleate (intact and as MK‐422) was 94%. Recovery of MK‐521 was 97%. These results indicate lack of significant metabolism of these agents, apart from the bioactivation of enalapril.
Lovastatin is a prodrug lactone whose open-chain 3,5-dihydroxy acid is a potent, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis. The compound undergoes extensive and complex metabolism in animals and humans, with the metabolites excreted predominantly in bile. Radiochromatograms of bile from three human subjects and of bile and liver homogenates from mouse, rat, and dog displayed obvious species differences. Biotransformation of lovastatin occurred by three distinct routes, namely hydrolysis of the lactone ring to yield the pharmacologically active dihydroxy acid, cytochrome P-450-mediated oxidation of the fused-ring system, and beta-oxidation of the dihydroxy acid side chain. The first two reactions occurred in all four species, but the last was observed in mouse and rat only. The P-450 reactions, hydroxylation and a novel dehydrogenation reaction, yielded a 6'-hydroxylated metabolite of the dihydroxy acid and a 6'-exomethylene derivative as major and minor metabolites, respectively, in the bile of rat and dog. Human bile, which contained predominantly polar metabolites, yielded these metabolites in similar proportions only after mild hydrolysis at pH 5.0. In mouse and rat an atypical beta-oxidation of the dihydroxy acid side chain occurred to give a pentanoic acid derivative that was observed in liver homogenates. This metabolite was subsequently conjugated with taurine and excreted in the bile. From these studies, cytochrome P-450 oxidation is the primary route of phase I metabolism for lovastatin in human and dog, but beta-oxidation plays a major metabolic role in rodents.
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