D. A. Willard

Disposition of captopril in normal subjects

The disposition of Captopril, an angiotensin‐converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100‐mg tablet of 35S‐labeled drug. Average absorption parameters for unchanged Captopril in blood were Tmax 0.93 ± 0.08 hr and Cmax 800 ± 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 ± 0.08 hr and Cmax 1,580 ± 90 ng/ml (as Captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of Captopril: time, elimination half‐life (t½) of unchanged drug could not be determined. At 1 hr unchanged Captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of Captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24‐hr urine sample (66% of the dose) was 58% Captopril (38% of dose), 2% Captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia

The pharmacokinetics, pharmacodynamics, and safety of pravastatin, a new selective 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, were evaluated during monotherapy and with subsequent concomitant cholestyramine therapy in 33 patients with primary hypercholesterolemia in this randomized study. After 4 weeks, pravastatin monotherapy (5 mg, 10 mg, and 20 mg twice daily) significantly decreased total cholesterol by 17% to 24% (p < 0.001 versus baseline) and low‐density lipoprotein cholesterol by 23% to 35% (p < 0.001). High‐density lipoprotein cholesterol increased by 8% to 9%, and triglycerides decreased by 6% to 9%. The area under the serum concentration‐time curve and maximum serum concentration of pravastatin showed dose‐proportionality; time to maximum serum concentration and serum elimination half‐life were independent of dose. When added to pravastatin therapy, cholestyramine enhanced the lipid‐lowering effects of pravastatin. After 4 weeks of combination therapy, total cholesterol was reduced by 32% to 38% (p < 0.001 versus baseline), and low‐density lipoprotein cholesterol was reduced by 47% to 56% (p < 0.001). High‐density lipoprotein cholesterol increased by 11% to 18% (p < 0.05). Pravastatin was well tolerated; no clinical adverse events directly attributable to the drug were reported.

Metabolic Studies in Patients with Nadolol: Oral and Intravenous Administration

Nadolol-14C, 2,3-cis-5-(3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy)-1,2,3,4-tetrahydro-2,3-naphthalenediol, a nonselective beta-adrenergic blocking agent, was administered orally and intravenously at 2-mg doses to patients with mild cases of essential hypertension. Terminal plasma half-times after oral and intravenous doses were an average of 12.2 and 9.8 hours, respectively. After oral doses, an average of 24.6 and 76.9 per cent of the dose was excreted in urine and feces, respectively, whereas, after intravenous doses, an average of 72.9 and 23.3 per cent of the dose was excreted by the same routes. Calculations of absorption, based on urinary excretion and on areas under the plasma concentration-versus-time curves, indicated that oral doses of nadolol-14C were absorbed to the extent of 33.6+/-2.4 per cent (+/- S.E.). The average overall volume of distribution after intravenous administration was 2.09+/-0.51 1./kg (+/- S.E.), and the average volume of the central compartment was 0.30+/-0.04 1./kg. Only unchanged nadolol-14C was excreted in the urine and feces of patients after either oral or intravenous administration of the drug.

Renal handling of captopril: Effect of probenecid

14C‐Captopril was given intravenously to four normal subjects in a 4‐mg priming dose followed by constant intravenous infusion of 1.7 mg/hr for 3.5 hr with and without concomitant probenecid. Steady‐state levels of unchanged captopril were obtained between 1.5 and 3.5 hr. In the presence of probenecid, the average steady‐state blood levels of total radioactivity were higher (36%) than on captopril alone. Unchanged captopril levels were slightly higher (14%) in the presence of probenecid. Kinetic evaluations were carried out exclusively on data for unchanged captopril. The average total body clearance (ClT) and renal clearance (ClR) of captopril in the absence of probenecid were 775 and 388 ml/kg/hr. The corresponding values for captopril with probenecid (631 and 217 ml/kg/hr) were lower. The average ratio of ClR to ClT for captopril alone was 0.50 and fell to 0.35 in the presence of probenecid. When captopril alone was given, a minimum of 78% of the renal excretion of captopril during steady‐state could be attributed to net tubular secretion, but when captopril was given with probenecid, net tubular secretion was only 57%. The volume of distribution of captopril during steady state was not altered by probenecid. For the first 3.5 hr, cumulative renal excretion of total radioactivity with and without probenecid was 55% and 60%, but cumulative excretion of unchanged captopril was higher after captopril alone (36% of dose) than after the combination (21% of dose).

Pharmacokinetics of Nadolol, a Beta-Receptor Antagonist: Administration of Therapeutic Single- and Multiple-Dosage Regimens to Hypertensive Patients

(Corgard*), 2,3-cis-5-[3-[ (1, .1 ‘ 1-dimethylethyl) amino] -2-hydroxypropoxy] 1,2,3,4-tetrahydro-2,3-naphthalene diol, is a clinically effective beta-adrenergic blocking agent in the treatment of hypertension and angina.1 In studies in cats and dogs2 as well as in man,3 nadolol was also active against cardiac arrhythmias. In contrast to propranolol, nadolol is devoid of local anesthetic activity and does not depress the canine heart.4 Extensive preclinical toxicologic studies in animals have demonstrated that nadolol has a low order of toxicity.5 An earlier study#{176} compared the metabolic disposition of single oral and intravenous 2-mg doses of nadolol given to mildly hypertensive patients. Since such small oral doses were considered to have little, if any, therapeutic activity, the present study was undertaken with a dose of 80 mg, one known to be thera-

Influence of Probenecid and Food on the Bioavailability of Cephradine in Normal Male Subjects

604 The Journal of Clinical Pharmacology C EPHRADINE is a new broad-spectrum semisynthetic cephalosporin antibiotic, 7 [D(-) amino 2 (1,4 c3-clohexadien 1 yl)acctamido 3 methyl8 oxo 5 thia 1 azabicyclo[4.2.0J oct-2-ene-2-carboxylic acid. Cephradine has demonstrated a broad spectrum o antimicrobial activity against both Grampositive and Gram-negative organisms.1 It is the first cephalosporin agent available for oral, intramuscular, and intravenous administration. Cephradine has demonstrated complete and rapid absorption as well as rapid renal elimination when administered to human subjects.1’2 availability of cephradine given either orally or by intramuscular injection.

Endocrine and Cardiovascular Consequences of Angiotensin Converting Enzyme Inhibition

One of several novel peptidic inhibitors of angiotensin converting enzyme (CEI) has been studied intravenously both in normal male volunteers and severely hypertensive patients without any clinically significant adversity or intolerance. Hypertensive patients experienced a significant yet gradual reduction in resting arterial pressure without hypotension. The addition of a diuretic agent was observed to potentiate this antihypertensive effect. Normal, sodium replete volunteers received this nonapeptide intravenously in doses up to 2·0 mg/kg without any significant cardiovascular effect. Both patients and normal subjects exhibited reversible dose related increases in angiotensin I and renin levels after receiving the peptide. The plasma renin response to tilting was also potentiated by CEI. These findings suggest that intravenous CEI may be of value in the treatment of severely elevated hypertension and as a tool to evaluate vasoconstrictor and volume factors in hypertension.

Pharmacokinetics, safety, and pharmacologic effects of fosinopril sodium, an angiotensin-converting enzyme inhibitor in healthy subjects.

The pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin‐converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril. In a dose‐tolerance study (study II), 80 and 160 mg of the drug were administered in doses of 40 mg bid and 80 mg bid for 2 weeks. Pharmacokinetics were determined on days 1 and 14, and blood pressure and ACE activity were measured daily. One hour after all doses of fosinopril, serum ACE activity was undetectable. Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed. ACE activity remained undetectable for more than 24 hours after the treatment was stopped in study II. Serum aldosterone levels were decreased by 50% of baseline values in both studies. In study I, maximal reductions in mean blood pressure occurred approximately 6 hours postdose; once‐daily doses of 20 mg or greater achieved reductions of 11.3 to 21.6% (P < .05, compared with placebo reductions). Fosinopril was well tolerated. Subjects reported only mild gastrointestinal complications at doses of 80 mg/day or higher. These data show that fosinopril is a safe and effective inhibitor of ACE with a long duration of action on serum ACE activity.

Efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia

PURPOSE Patients with type I and type II diabetes mellitus have an increased risk of coronary heart disease. In many diabetics, hypercholesterolemia is present and further exacerbates this risk. We investigated the efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia. PATIENTS AND METHODS In this 24-week, multi-center, double-blind, placebo-controlled study, 94 patients (45 men, 49 women), 18 to 70 years of age, with type I or type II diabetes mellitus and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol [LDL-C] levels > 150 mg/dL and above the 75th percentile for the US population by age and gender) were randomized to receive pravastatin 20 mg hs or matching placebo. Two patients were randomized to treatment with drug for every 1 randomized to placebo. The dose could be doubled after 10 weeks, and cholestyramine or colestipol could be added after 18 weeks, as needed, to attempt to lower the LDL-C levels to below the 50th percentile for the US population. RESULTS Significant reductions in LDL-C (-27.6%), total cholesterol (-22.1%), very-low-density lipoprotein cholesterol (-22.6%), and triglycerides (-12.8%) (P < or = 0.001 versus placebo for all reductions), and significant increases in high-density lipoprotein cholesterol (4.4%) (P < or = 0.05 versus placebo) were noted in the pravastatin treatment group (average dose 29.5 mg) at 16 weeks. The beneficial lipid-lowering effects of pravastatin were maintained throughout the 24 weeks of the study. Pravastatin was well tolerated, and the frequency of side effects was similar in the pravastatin and placebo groups. No clinically significant changes in the control of diabetes, as assessed by fasting blood glucose levels and glycosylated hemoglobin measurements, were seen during this study. CONCLUSION The results of this study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with type I or type II diabetes mellitus and hypercholesterolemia.

Quantitation of drug levels and platelet receptor blockade caused by a thromboxane antagonist.

SQ 28,668 is a structural analog of thromboxane A2. It inhibits the effects of thromboxane in vitro. Fifty‐six healthy male subjects were given either placebo or three equal daily doses of SQ 28,668 ranging from 25 to 1200 mg. Plasma drug concentrations increased in a dose‐dependent manner. The shape of the plasma drug concentration‐time curve was consistent with enterohepatic recirculation. The effects of SQ 28,668 on ex vivo platelet aggregation suggested that SQ 28,668 is a specific competitive antagonist of thromboxane A2 with a platelet receptor dissociation constant (estimated by Schild analysis) of about 19 nmol/L. Approximately 94% occupation of thromboxane receptors by SQ 28,668 was required to produce a small but measurable increase of the template bleeding time. Dose‐ranging studies of antithrombotic drugs are difficult and expensive. For this reason, a method was developed that allows estimation of the dose of a thromboxane receptor antagonist that would be expected to be therapeutically equivalent to a given dose of aspirin.