Influence of food on the bioavailability of enalapril.

In a randomized, two-period crossover study in 12 normal volunteers, serum and urine concentrations of the angiotensin-converting enzyme inhibitor enalapril and its active metabolite enalaprilat were determined following administration of a single 40-mg tablet of enalapril maleate administered both in the fasting state and with a standard breakfast. A 7-d interval separated the two treatment periods. Area under the serum concentration-time curves for enalaprilat and urinary recoveries for enalaprilat and total drug did not differ significantly between the fed and fasted conditions. The mean observed maximum serum concentration of enalaprilat was slightly higher for the fasting treatment, but the time to peak concentration was almost identical for the two treatments. Enalapril maleate is unlike the prototype angiotensin-converting enzyme inhibitor captopril in that a standard meal does not appear to influence absorption of this new drug.

Renal excretion of pseudoephedrine in the rat.

Pseudoephedrine is an organic base used in the treatment of upper respiratory tract disorders. Surgical techniques and experimental procedures were developed to study the renal elimination mechanisms for this drug in the rat. The ability to measure renal clearance accurately and to demonstrate renal secretion by a carrier-mediated transport system was verified by comparing results from N'-methylnicotinamide (NMN) excretion studies with literature results. Renal tubular secretion of NMN was shown to be saturable and was inhibited by mepiperphenidol to the same extent as that reported in the literature. Pseudoephedrine was cleared by the kidney at a rate in excess of inulin and close to or possibly greater than renal plasma flow. In addition to filtration and secretion, pseudoephedrine appeared to be subject to pH dependent passive reabsorption. When the secretion of pseudoephedrine was studied in detail, it was found to be nonsaturable for plasma levels of pseudoephedrine ranging from 0.16 to 1.5 microgram/ml. Secretion, however, was inhibited by mepiperphenidol suggesting a carrier-mediated process.

Pseudoephedrine pharmacokinetics in the rat using a microanalysis technique.

A microanalytical procedure was developed using a gas chromatographic-electron capture technique which is capable of detecting 2 ng pseudoephedrine in 20 microliter plasma samples. Standard curves for pseudoephedrine are linear over the concentration range 0.1--1.6 microgram/ml. Plasma and urine concentrations of pseudoephedrine were followed in 3 rats after intravenous dosing. Derived pharmacokinetics parameters exhibited little inter-animal variation. Average plasma clearance was 67.6 ml/min/kg, with renal clearance averaging 30.3 ml/min/kg. This latter value is approximately 4X the glomerular filtration rate in the rat.

The pharmacokinetics of lisinopril in hospitalized patients with congestive heart failure.

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.

The cutaneous microflora of adolescent, persistent and late-onset acne patients does not differ.

The cutaneous microbiology and antibody status to Propionibacterium acnes of patients with persistent (males, n = 32; females, n = 33) and late-onset (females, n = 25) acne were compared with individuals with adolescent acne (males, n = 22; females, n = 18) and normal control volunteers (persistent acne: males, n = 26; females, n = 30; late-onset: females, n = 20). Males had significantly higher grades of acne compared with females (P < 0.05). The microflora consisted in the main of propionibacteria, staphylococci and Malassezia; other bacteria represented less than 0.01% of the total microflora. At all sites for all samples there were significantly more propionibacteria than staphylococci or Malassezia (P < 0.05). There were significantly higher (P < 0.05) numbers of microorganisms in follicular casts from patients compared with their control volunteers for female facial skin and male back skin. Twenty-six papules and 48 normal follicles were analysed. A bimodal distribution of microbial colonization was noted, with about 90% of normal follicles and about 10% of acne follicles having no detectable viable microorganisms. Anti-P. acnes IgG antibody titres were measured using a secondary fluorescein isothiocyanate antibody technique, and no significant differences in titre were found between any groups of patients (P > 0.05). Correlation analysis showed no association between the population densities of P. acnes and anti-P. acnes IgG titres. There were no differences in the microbiology of skin of adolescent acne patients, persistent acne patients or late-onset acne patients which could account for these various forms of acne.

Comparative clinical pharmacology of intravenous cefoxitin and cephalothin.

Intravenous doses of 0.5, 1, and 2 g cephalothin and cefoxitin, a semi-synthetic cephamycin antibiotic highly resistant to bacterial cephalosporinase, were infused over a period of 3 minutes into 18 normal adult males by a randomized, crossover design. Serum and urine data on cefoxitin best fit a two-compartment open model. Serum concentrations following cefoxitin were higher and more prolonged and urine recoveries higher than those following equal doses of cephalothin. The terminal serum half-life of cefoxitin was longer at all dose levels. Renal clearance of cephalothin-like activity exceeded that of cefoxitin, which may possess dose-dependent kinetics. Whereas cephalothin has been reported to metabolize by greater than 35% to the less active desacetyl form, cefoxitin was metabolized by 0.1 to 6% to the descarbamyl form in individual subjects.

Serum concentrations of ampicillin and probenecid and ampicillin excretion after repeated oral administration of a pivampicillin-probenecid salt (MK-356).

Twenty male volunteers received oral doses (2100, 1050, and 525 mg) of a pivampicillin-probenecid salt in a 1 to 1 molar ratio (MK-356) at 12 hour intervals. After each dose peak serum concentrations of probenecid were observed 2 hours later than peak concentrations of ampicillin. Following the first dose of MK-356 the apparent elimination rate of ampicillin was dose-dependent and did not follow first order kinetics, as it showed a longer apparent half life after a higher dose. An equal dose of MK-356 administered 12 hours later caused an increase in the peak serum ampicillin level greater than expected from the concentration of ampicillin after the preceding dose. In twelve male volunteers who received at random 525 mg of MK-356 or 350 mg of pivampicillin, each three times daily for 4 days, the areas under the ampicillin concentration curve were the same after the first or last dose of either drug. When 2100 or 1050 mg of MK-356 was taken as an initial dose, 30 to 40 per cent of the ampicillin was recovered from urine in the ensuing 12 hours. The results indicate that when at least 400 mg probenecid was coadministered twice daily with 700 mg pivampicillin (MK-356), the peak serum concentrations of ampicillin were increased and its elimination rate slowed following successive doses.

Effects of rate of infusion and probenecid on serum levels, renal excretion, and tolerance of intravenous doses of cefoxitin in humans: comparison with cephalothin.

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 mug/ml, respectively, and after cefoxitin infusions they were 27, 74, 115, and 125 mug/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.

Effects of repeated doses of enalapril on renal function in man.

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)

Evidence for route dependent biotransformation of cyclobenzaprine hydrochloride.

Cyclobenzaprine hydrochloride was administered to healthy volunteers as a 10 mg oral tablet, 10 mg and 20 mg intramuscular injections, and a 10 mg intravenous injection. Urinary excretion and plasma level data for cyclobenzaprine together provide evidence for route dependent biotransformation. Urinary excretion of total cyclobenzaprine (unchanged plus the glucuronide conjugate) was greater for the oral treatment than for the parenteral treatments (i.m. and i.v.). Area under the plasma concentration-time curve for unchanged cyclobenzaprine, however, was less for the oral treatment than for the parenteral treatments. Based on area calculations, the bioavailability of the 10 mg oral tablet, 10 mg i.m. and 20 mg i.m. injection was 0.33, 0.76, and 0.56, respectively, when compared to the 10 mg i.v. injection of cyclobenzaprine hydrochloride. The four treatments were well tolerated and no clinically adverse effects were observed.

Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers.

When three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin-converting enzyme (ACE). The half-life for the terminal phase (approximately 40 h) was not predictive of steady-state parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half-life for accumulation was 12.6 h. The mean accumulation ratio was 1.38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.

Biotransformation of lovastatin. V. Species differences in in vivo metabolite profiles of mouse, rat, dog, and human.

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.

The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.

Pharmacokinetics of repeated single oral doses of enalapril maleate (MK-421) in normal volunteers.

Enalapril, the ethyl ester of a potent angiotensin converting enzyme inhibitor, enalaprilat, was administered to healthy volunteers as a capsule containing 10 mg of the maleate salt, every 24h for eight doses. Serum profiles show little accumulation of enalaprilat following eight daily doses of enalapril maleate. An average effective half-life for accumulation of approximately 11h was calculated from urine data. Comparison of observed 24-h urinary recoveries of enalaprilat to predicted steady-state recovery indicates that an 'average' steady state for enalaprilat is attained by the third or fourth dose of enalapril maleate. Statistical comparison of daily urinary recoveries, as well as Cmin values for enalaprilat, confirm this. Observed fluctuations in serum and urine data during apparent steady state suggest some day-to-day variability in the absorption of enalapril maleate and/or its hydrolysis to enalaprilat. An accumulation ratio of 1.3 for enalaprilat was calculated from the predicted steady-state urinary recovery and observed urinary recovery for dose one.

Enalapril maleate and a lysine analogue (MK-521): disposition in man.

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 versus bezafibrate: efficacy, tolerability, and effect on urinary mevalonate.

Lovastatin and benzafibrate have proved effective in lowering low-density-lipoprotein (LDL) cholesterol and elevating high-density-lipoprotein (HDL) cholesterol. We compared their tolerability, safety, and effects on lipoproteins and urinary mevalonate excretion in a short-term study. Forty patients with primary hypercholesterolemia were enrolled in a single-blind randomized study with a diet/placebo period of 8 weeks and a treatment period of 12 weeks. Twenty patients received lovastatin (final average dose 70.5 mg/day), and 20 patients received bezafibrate 400 mg/day. LDL cholesterol was lowered by 35% (from 323 to 208 mg/dl) with lovastatin and by 8% (from 289 to 264 mg/dl) with benzafibrate. HDL cholesterol increased by 21 and 20% with lovastatin and benzafibrate, respectively. Twenty-four-hour urinary mevalonic acid output decreased by 37% during treatment with lovastatin and by 2% during treatment with bezafibrate. Thus, the lowering of cholesterol by lovastatin, but not by bezafibrate, can be attributed to inhibition of HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase. Both lovastatin and bezafibrate are well tolerated.