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Electrocardiographic (ECG) recordings from 3 placebo-controlled thorough QT healthy volunteer studies were used to compare QT intervals obtained by manual measurement with those generated by ECG machines. The effect of the positive control was compared to placebo at each time point for data obtained from both sources. Both manual and automated techniques consistently demonstrated statistically significant prolongation of QTcF with the positive controls. The proportion of outlier values was small for both methods. The pairwise comparison between manual and automated uncorrected QT intervals demonstrated clear differences, with intervals derived from one machine on average 16 to 19 milliseconds shorter and from the other 7 milliseconds longer than the manually measured QT intervals, but these differences disappeared when analyzing QT change from baseline. Both manual and automated, commercially available QT algorithms demonstrated small statistically significant effects on the QTc interval induced by positive controls. [ABSTRACT FROM AUTHOR]

Background: Increased consumption of the lipogenic sugar fructose promotes the current epidemic of metabolic disease. Ketohexokinase (KHK) catalyzes the first committed step in fructose metabolism. In animal models, KHK inhibition decreases hepatic de novo lipogenesis and steatosis and corrects many metabolic abnormalities associated with insulin resistance. The consequences of inhibiting fructose metabolism in humans have not been tested. This randomized, double-blind, placebo-controlled, phase 2a study (NCT03256526) assessed the effect of the reversible KHK inhibitor PF-06835919 on metabolic parameters in participants with non-alcoholic fatty liver disease (NAFLD)., Methods: Adults with NAFLD (>6% whole liver fat [WLF] by magnetic resonance imaging-proton density fat fraction) received once-daily oral placebo or PF-06835919 75 mg or 300 mg for 6 weeks. Randomization (1:1:1) was via computer-generated randomization code with random permuted blocks. Endpoints included WLF (primary endpoint), safety/tolerability, and metabolic parameters., Findings: Overall, 158 participants were screened and 53 randomized; 48 completed the trial (placebo, n = 17; PF-06835919 75 mg, n = 17; PF-06835919 300 mg, n = 14). Compared with placebo, significant reductions in WLF were observed in participants receiving PF-06835919 300 mg (difference of -18.73%; p = 0.04), but not with 75 mg. In addition, inhibition of KHK resulted in improvement in inflammatory markers. The incidence of treatment-emergent adverse events (AEs) was low and similar across treatment groups (26.3%, 23.5%, and 29.4% of participants in the placebo and PF-06835919 75 mg and 300 mg groups, respectively). No serious AEs were reported., Conclusions: Data suggest that KHK inhibition may be clinically beneficial in the treatment of adults with NAFLD and insulin resistance., Funding: This study was sponsored by Pfizer Inc., Competing Interests: Declaration of interests D.J.K., K.C., V.R.S., A.J.B., M.J.B., and R.A.C. are employees and stakeholders of Pfizer Inc., (Copyright © 2021. Published by Elsevier Inc.)

1. The absorption, metabolism, and excretion of a single oral 450-mg dose of [ 14 C]-( S )-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1 H -imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator, was investigated in humans. Mass balance was achieved with ∼94.6% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 70.6% and 24.1%, respectively. Unchanged PF-04991532 collectively accounted for ∼47.2% of the dose excreted in feces and urine, suggestive of moderate metabolic elimination in humans. 2. The biotransformation pathways involved acyl glucuronidation (M1), amide bond hydrolysis (M3), and CYP3A4-mediated oxidative metabolism on the cyclopentyl ring in PF-04991532 yielding monohydroxylated isomers (M2 a - d ). Unchanged PF-04991532 was the major circulating component (64.4% of total radioactivity) whereas M2 a - d collectively represented 28.9% of the total plasma radioactivity. 3. Metabolites M2 a - d were not detected systemically in rats and dogs, the preclinical species for the toxicological evaluation of PF-04991532. In contrast, cynomologus monkeys dosed orally with unlabeled PF-04991532 revealed M2 a - d in circulation, whose UV abundance was comparable to the profile in humans. This observation suggested that monkeys could potentially serve as a non-rodent alternative for studying the toxicity of PF-04991532 and its metabolites M2 a - d . 4. The present results are in excellent agreement with our previously generated metabolite scouting data, which provided preliminary evidence for the disproportionate metabolism of PF-04991532 in humans.

PF-04991532 ((S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato-selectivity via organic anion-transporting polypeptides (OATP)s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of OATP1B1/1B3 inhibition and renal impairment on PF-04991532 oral pharmacokinetics. Cyclosporine (600 mg single dose) increased mean area under the plasma curve (AUC) of PF-04991532 by approximately threefold in healthy subjects. In a renal impairment study, PF-04991532 AUC values were ~ 2.3-fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically-based pharmacokinetic (PBPK) model parameterizing hepatic and renal transporter-mediated disposition based on in vitro inputs, and verified using first-in-human data, indicated the key role of OATP-mediated hepatic uptake in the systematic and target-tissue exposure of PF-04991532. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~ 35%) and renal organic anion transporter (OAT)3 (80-90%) function with renal impairment. This study illustrates the adequacy and utility of the PBPK approach in assessing the impact of drug interactions and kidney dysfunction on transporter-mediated disposition., (© 2019 Pfizer Inc. Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Aims: To conduct a dose-response assessment of the efficacy and safety of the glucagon receptor antagonist PF-06291874 in adults with type 2 diabetes (T2DM) using stable doses of metformin., Materials and Methods: This randomized, double-blind, statin-stratified, placebo-controlled, 4-arm, parallel-group study was conducted in patients with T2DM who were receiving background metformin. After an 8-week, non-metformin oral antidiabetic agent washout period, 206 patients were randomized to placebo or PF-06291874 (30, 60 or 100 mg once daily) for 12 weeks. Glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and safety endpoints were assessed at baseline and post baseline., Results: Dose-dependent mean reductions from baseline in HbA1c for PF-06291874 ranged from -0.67% (-7.29 mmol/mol) to -0.93% (-10.13 mmol/mol), and for FPG from -16.6 to -33.3 mg/dL after 12 weeks of dosing. The incidence of hypoglycaemia was low and was similar between groups receiving PF-06291874 and placebo. Small, non-dose-dependent increases in LDL cholesterol (<10%) and blood pressure (BP) (systolic BP > 2 mm Hg; diastolic BP > 1 mm Hg) were observed with PF-06291874. Modest non-dose-dependent median increases were observed across PF-06291874 groups at 12 weeks for alanine aminotransferase (range, 37.6-48.7 U/L vs placebo) and aspartate aminotransferase (range, 33.3-36.6 U/L vs placebo); these were not associated with bilirubin changes. Small increases were observed in body weight (< 0.5 kg) in each PF-06291874 group vs placebo., Conclusions: In patients with T2DM, PF-06291874 significantly lowered HbA1c and glucose, was well tolerated and carried a low risk of hypoglycaemia. Small, non-dose-related increases in BP, lipids and hepatic transaminases were observed., (© 2018 John Wiley & Sons Ltd.)

Aims: The glucagon receptor antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM., Methods: After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150mg once daily for 28days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28., Results: Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8mg/dL and in FPG from 27.1 to 57.2mg/dL after 28days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3×upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia., Conclusions: PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4weeks of dosing in subjects with T2DM., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM)., Methods: Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured., Results: PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated., Conclusion: PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia., (© 2016 John Wiley & Sons Ltd.)

Objective: Our objective was to compare simvastatin with the validated probe midazolam in the assessment of cytochrome P450 (CYP) 3A activity., Methods: This study used an open-label, fixed-sequential, 3-way crossover study design. Nineteen subjects received oral doses of 0.075 mg/kg midazolam and 40 mg simvastatin during 3 phases (baseline, after inhibition with 400 mg ketoconazole for 10 days, and after induction with 600 mg rifampin [INN, rifampicin] for 9 days). Serial plasma concentrations of midazolam and simvastatin were obtained. Oral clearances of midazolam and simvastatin were compared., Results: Oral midazolam clearance decreased after pretreatment with ketoconazole (from a geometric mean of 25 mL x min(-1) x kg(-1) [range, 12-57 mL x min(-1) x kg(-1)] to 2.7 mL x min(-1) x kg(-1) [range, 1.2-8.5 mL x min(-1) x kg(-1)], P < .001) and increased after pretreatment with rifampin (to a geometric mean of 203 mL x min(-1) x kg(-1) [range, 125-371 mL x min(-1) x kg(-1)], P < .001). Oral simvastatin clearance decreased after ketoconazole (from a geometric mean of 312 mL x min(-1) x kg(-1) [range, 151-1478 mL x min(-1) x kg(-1)] to 25 mL x min(-1) x kg(-1) [range, 8.0-147 mL x min(-1) x kg(-1)], P < .001) and increased after rifampin (to a geometric mean of 3536 mL x min(-1) x kg(-1) [range, 413-10,329 mL x min(-1) x kg(-1)], P < .001). The change in simvastatin clearance was highly variable from baseline to inhibition (6- to 33-fold decrease) and from baseline to induction (2- to 39-fold increase) compared with midazolam (7- to 18-fold decrease during inhibition and 4- to 12-fold increase during induction). Midazolam and simvastatin oral clearances were correlated for all study phases (r = 0.5 and P = .03 for baseline and r = 0.53 and P = .02 for inhibition) but were weakest for induction (r = -0.031, P = .22). The area under the concentration-time curve inhibitory ratio for midazolam was 9.4 versus 12.4 for simvastatin (r = 0.3, P = .03)., Conclusions: Compared with midazolam, simvastatin is a nonvalidated, suboptimal probe for studying CYP3A drug interactions because of its lack of CYP3A specificity.

Small sample sizes are typically incorporated in early Phase I clinical studies, which may lead to insignificant changes in safety parameters such as blood pressure. Therefore, it is paramount to identify an optimal, noninvasive method of accurately measuring blood pressure and an appropriate analysis strategy yielding the smallest variability. The goals of this study were (1) to compare the variability between automated and manual blood pressure measurements, (2) to determine whether triplicate blood pressure measurements were independent of one another, and (3) to assess how the number of blood pressure readings affects variability and study sample size. Twenty healthy volunteers were enrolled in this randomized, two-way crossover study. Each subject received three incremental infusions of phenylephrine or normal saline on separate days to simulate blood pressure variability. The mean systolic blood pressure readings with the automated device were consistently higher than the manual device by 3 to 5 mmHg. Conversely, the mean diastolic blood pressure readings with the automated device were consistently 3 to 5 mmHg lower than the manual device. However, the variability and absolute change in blood pressure were essentially identical with manual and automated methods. No systematic order effects such as the first blood pressure reading always being higher were detected, suggesting that the triplicate readings were independent of one another and that an interval of 2 minutes between readings is adequate. Compared to a single measurement, collecting blood pressure in triplicate results in a 40% lower sample size needed to detect a 5-mmHg difference in systolic blood pressure.

Objective: To review the role of homocysteine as a risk factor in the pathogenesis of atherosclerosis and to provide recommendations for the treatment of hyperhomocysteinemia., Data Sources: A MEDLINE search using key terms such as homocysteine, atherosclerosis, folic acid, vitamin B6, and vitamin B12 was conducted for the time period 1966 through January 1999., Study Selection: An article was selected for inclusion in this review if it assessed the relationship and proposed mechanisms of hyperhomocysteinemia on the vasculature, physiologic changes due to hyperhomocysteinemia, and outcomes due to hyperhomocysteinemia, such as morbidity and mortality. In addition, studies that assessed the treatment outcomes of hyperhomocysteinemia were evaluated., Data Synthesis: Studies of patients with cerebral vascular disease reveal elevated homocysteine concentrations in 30-40% of patients compared with controls. Many studies demonstrate a correlation between elevated homocysteine concentrations, risk of myocardial infarction, and mortality. In addition, hyperhomocysteinemia and decreased folic acid concentrations have been identified in end-stage renal disease (ESRD) and type 2 diabetic patients, while both concentrations remained normal in healthy controls. Studies using folic acid 650 microg/d reduced homocysteine concentrations to within normal therapeutic range after two weeks of treatment. Studies with vitamins B6 and B12 have demonstrated that the use of either alone is ineffective, but when combined or administered with folic acid, homocysteine concentrations return to normal. All therapies must be given for the lifetime of the patient. In addition, patients must use discretion in their diet, as common beverages, such as coffee, have a strong correlation with hyperhomocysteinemia, while foods high in folic acid, vitamin B6 and vitamin B12 may reduce homocysteine concentrations. Additional prospective studies are needed to determine effects of treatment of hyperhomocysteinemia and various diets on atherosclerotic morbidity and mortality., Conclusions: Studies demonstrate a positive correlation between hyperhomocysteinemia and atherosclerosis. The treatment of choice for hyperhomocysteinemia is folic acid. Although the optimal dose is not known, 650 microg/d is the minimum effective dose. To date, no studies have assessed the effects on morbidity and mortality when treating high homocysteine concentrations in atherosclerotic patients.

Objective: To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers., Methods: Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled., Results: Men and women showed stereoselective pharmacokinetics; (S)-metoprolol concentrations were significantly greater than those for (R)-metoprolol for both groups. Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve). No differences were observed between genders with respect to elimination half-life. Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20)., Conclusions: Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.

A series of clinical pharmacology studies was conducted to characterize potential interactions between eprosartan and other commonly prescribed drugs. Separate studies assessed the effect of eprosartan on the pharmacokinetics of digoxin and hydrochlorothiazide (HCTZ) and the pharmacodynamics of warfarin and glyburide (glibenclamide), as well as the effects of ranitidine, HCTZ, fluconazole, and ketoconazole on eprosartan pharmacokinetics. Eprosartan had no significant effect on the pharmacokinetics of digoxin and HCTZ and the pharmacodynamics of warfarin and glyburide. Thus, no dosing adjustments are necessary during concomitant therapy with these agents. Ranitidine, HCTZ, ketoconazole, and fluconazole had no effect on eprosartan pharmacokinetics. Single or multiple oral doses of eprosartan were safe and well tolerated when coadministered with these agents.

Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of warfarin.

This study was conducted to determine whether gender differences exist in adrenergic receptor sensitivity and baroreflex response. Adrenergic receptor sensitivity was assessed by administering sequentially increasing intravenous doses of phenylephrine and isoproterenol. Baroreflex sensitivity was determined from the slope of pulse intervals plotted against phenylephrine-induced rise in systolic blood pressure (SBP). Drug-induced changes in heart rate, blood pressure, and brachial artery diameter were measured and statistically compared. Women required a lower infusion rate of phenylephrine to increase SBP by 20 mmHg from baseline. There were no statistically significant gender-related differences in baroreflex sensitivity. The dose of isoproterenol needed to increase heart rate by 25 beats per minute from baseline also did not differ significantly between groups. Percent changes from baseline in brachial artery diameters in response to phenylephrine also were similar between groups. These data suggest that women may have greater alpha-adrenergic receptor sensitivity than men, whereas beta1-adrenergic receptor sensitivity is similar between genders. A trend toward a greater baroreflex sensitivity in men than in women was also observed. This study also provides evidence for a possible relationship between adrenergic receptor sensitivity and baroreflex sensitivity.

Twelve patients with type II diabetes and 12 age-, weight-, and gender-matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 Cmax, tmax, AUC0-24, and Cl/F values of troglitazone were 1.54 micrograms/mL, 3.25 hours, 15.6 micrograms.hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 micrograms/mL, 2.63 hours, 12.5 micrograms.hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady-state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.

Objective: To investigate the effect of steady-state fluconazole administration on the disposition of eprosartan, losartan, and E-3174., Methods: Sixteen healthy male subjects received 300 mg eprosartan every 12 hours, and 16 received 100 mg losartan every 24 hours on study days 1 to 20. All 32 subjects received 200 mg fluconazole every 24 hours beginning on day 11 and continuing through day 20. Serial blood samples were collected over one dosing interval on study days 10 and 20 for measurement of plasma concentrations of eprosartan, losartan, and E-3174 (the active metabolite of losartan)., Results: There was no significant difference in eprosartan area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUC(0-t)] or maximum concentration (Cmax) when administered alone and with fluconazole. After concomitant administration with fluconazole, losartan AUC(0-t) and Cmax were significantly increased 66% and 30%, respectively, compared with those values for losartan alone. The AUC(0-t) and Cmax for E-3174 were significantly decreased 43% and 56%, respectively, after administration of losartan with fluconazole., Conclusions: Fluconazole significantly increases the steady-state AUC of losartan and inhibits the formation of the active metabolite of losartan, E-3174. In contrast, fluconazole administration has no effect on the steady-state pharmacokinetics of eprosartan.

To evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15-minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but < or = 45%; n = 6), or severely impaired (ejection fraction < or = 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76-day period for estimation of pharmacokinetic parameters. With the exception of the half-life (t1/2) of DEA, statistical comparisons revealed no significant between-group differences in pharmacokinetic parameters or correlations between pharmacokinetic parameters and ejection fractions. The t1/2 of DEA was increased by approximately 60% in patients with severe left ventricular dysfunction compared with that in patients with moderately impaired and normal left ventricular function. The rate of DEA formation is slow, however, and its concentration relative to amiodarone is low. Therefore, it is unlikely that concentrations of DEA in serum would reach levels that contribute significantly to the pharmacologic activity of amiodarone during short-term (up to 2 weeks) intravenous amiodarone therapy. Single doses of amiodarone were well tolerated. The results of this study suggest that intravenous amiodarone can be used with appropriate observation to control arrhythmias, regardless of the degree of left ventricular dysfunction.

A study was conducted to characterize and compare the pharmacodynamics and pharmacokinetics of atenolol in young and elderly men. Six young (mean +/- SD, 25.0 +/- 3.0 years) and six elderly (63.0 +/- 3.2 years) healthy men took atenolol 100 mg orally once daily for 6 days. Heart rate response to submaximal exercise was measured at selected times for 48 hours, and plasma and urine samples were collected over the same time interval. The Sigmoid Emax model was fit to percent reductions in exercise heart rate and atenolol plasma concentrations. The younger men had significantly lower values for area under the steady-state plasma concentration-time curve and higher values for systemic clearance/F and renal clearance. EC50 values showed a trend toward greater sensitivity to the negative chronotropic effects of atenolol among the elderly men. Model-derived percent reductions in heart rate were greater at all concentrations among the elderly men. These data suggest that group differences in atenolol pharmacokinetics were likely a result of age-related decline in renal function, and that the elderly subjects were at least as sensitive as, and maybe even more sensitive than, the younger subjects to the negative chronotropic effects of atenolol.

We evaluated the effect of a high-fat breakfast and gastric emptying rate on the oral bioavailability of a isosoribide-5-mononitrate (5-ISMN) controlled-release tablet formulation (IMDUR 60-mg tablets, Astra Hässle AB, Mölndal, Sweden) relative to an oral solution in 18 healthy men. Gastric emptying was monitored by radiotelemetry using the Heidelberg capsule technique. After administration of the 5-ISMN 60-mg solution, absorption was rapid with mean peak plasma 5-ISMN concentrations of 1533 ng/mL achieved in less than 1 hour. In contrast, after administration of IMDUR 60-mg tablets, the drug was more slowly absorbed, reaching mean peak plasma concentrations of 541 ng/mL in 3 to 4 hours. The bioavailability of 5-ISMN from IMDUR tablets under fasted conditions was approximately 78% relative to the solution; and, in the presence of food, the bioavailability was slightly increased to 86% (P = .057). The mean gastric residence time of IMDUR tablets under fasted conditions was 68 minutes, and in the presence of food was increased to 478 minutes, with 9 of the 18 subjects having gastric emptying delayed for at least 600 minutes. We conclude that in the presence of food, gastric emptying time is considerably increased causing a delay in drug absorption and a slight increase in the bioavailability of 5-ISMN from this controlled-release tablet formulation, however this effect is not clinically relevant.

The effects of verapamil on the nephrotoxic potential of multiple-dose gentamicin were studied in healthy adult male volunteers. Subjects received a gentamicin infusion every 8 hours for 19 doses. Gentamicin dosage was adjusted to maintain peak concentrations of 5.5 mg/L and trough concentrations of 0.5 mg/L. Verapamil was given as a sustained release preparation of 180 mg twice daily starting 2 days before the aminoglycoside, and continued for 4 days post-gentamicin therapy. Nephrotoxicity was assessed by measuring 24-hour urinary alanine aminopeptidase excretion (AAP). The urinary AAP results of six subjects given gentamicin with verapamil were compared with urinary AAP from nine subjects treated with gentamicin alone. These nine subjects were matched with the verapamil-treated subjects on the basis of gentamicin area-under-the-curve (AUC). After matching AUC, gentamicin exposure was virtually identical between the two groups with an average gentamicin AUC of 26.61 +/- 1.49 and 27.51 +/- 1.25 mg.hr/L for the gentamicin/ve-rapamil and gentamicin only groups respectively. Verapamil retarded the rise in mean daily AAP excretion on days 1 to 6 of gentamicin therapy, with a significant difference with respect to AAP urinary excretion (P < .05) observed on day 2. There was no significant difference in total cumulative AAP excretion or in the time to return to baseline AAP excretion. Therefore, verapamil was effective in reducing AAP excretion associated with gentamicin therapy.

The effects of isradipine 2.5 mg and 5 mg on the disposition of theophylline were investigated in a placebo-controlled, randomized, three-way, crossover trial. Eleven healthy, nonsmoking men each received a treatment of placebo, and isradipine 2.5 mg and 5 mg every 12 hours for 6 consecutive days. On the morning of day 6, 2 hours after the isradipine dose, theophylline (solution) 5.0 mg/kg was administered orally, and blood samples were collected over 24 hours. A 2-week washout period separated treatment sequences. Plasma samples were analyzed for theophylline using high-performance liquid chromatography. Using a two-way analysis of variance, no significant changes in apparent theophylline clearance were observed between placebo, and isradipine 2.5 and 5 mg (0.815 +/- 0.164, 0.870 +/- 0.212, and 0.827 +/- 0.164 ml/min/kg, respectively; p = 0.136). Similarly, no significant change in volume of distribution was noted. These findings suggest that isradipine at recommended dosages does not impair theophylline metabolism.

Dilevalol is a novel antihypertensive drug that combines nonselective beta blockade with selective beta 2-receptor agonist activity. Its antihypertensive effect is mediated through arterial vasodilation and a decrease in systemic vascular resistance. At rest, dilevalol has little effect on heart rate or cardiac output. The drug is rapidly and completely absorbed but undergoes significant first-pass hepatic extraction. Its elimination half-life of approximately 12 hours allows for once-daily administration. In controlled clinical trials, dilevalol was at least as effective as angiotensin-converting enzyme inhibitors and comparable to beta blockers in antihypertensive efficacy. Preliminary data indicate that dilevalol reverses left ventricular hypertrophy in some patients. It does not adversely affect renal function and may have a favorable effect on plasma lipids, especially high-density lipoprotein cholesterol. The agent is usually well tolerated and may prove to be a useful addition to our antihypertensive drugs.

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p less than 0.05) and increased half-life from 12.7 to 15.9 hours (p less than 0.05). Diltiazem reduced the formation rate constants for 3-hydroxymethylantipyrine by 27% (p less than 0.05) and 4-hydroxyantipyrine by 37% (p less than 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 less than p less than 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half-life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.

The disposition of encainide is under genetic control. In extensive metabolizers, the drug undergoes extensive first-pass metabolism to form the active metabolites O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE). Because diltiazem is a known inhibitor of hepatic oxidative metabolism, the disposition of encainide and its metabolites was studied in eight extensive metabolizers and one poor metabolizer before and after administration of 90 mg diltiazem every 8 hours for 10 days. After diltiazem, the encainide serum AUC values increased in seven of the eight extensive metabolizers, and the percent recovery of encainide in urine increased by 69%. There were no apparent changes in the serum AUC values of the metabolites, suggesting that diltiazem may alter both the formation and the elimination clearances of the metabolites to a similar degree. In the poor metabolizer, encainide serum AUC increased 33% during treatment with diltiazem, but ODE and MODE could not be reliably quantitated. The subjects had no change in QRS, QTc, or JTc intervals after administration of diltiazem. Diltiazem inhibited the first-pass metabolism of encainide, resulting in increased bioavailability. This appeared to be caused by the inhibition of debrisoquin 4-hydroxylase and impairment of other unmeasured metabolic pathways for encainide. However, because no change occurs in the systemic exposure to the active metabolites, dosage adjustments in extensive metabolizers are probably not required for patients receiving combination encainide and diltiazem therapy.

A high-performance liquid chromatography (HPLC) procedure used to quantitate encainide and two of its active metabolites, O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE), is described. All three compounds were simultaneously extracted from urine and serum using an octyl (C-8) solid-phase extraction column. The compounds were then separated by reverse-phase HPLC on a cyanopropylsilane column using ultraviolet detection at 260 nm. Serum samples were quantified over a concentration range of 25-400 ng/ml and urine over a range of 150-10,000 ng/ml. Total run time for the assay was less than 12 min. Within-day and between-day precision and relative error were less than 10% in serum and less than 13% in urine for all three compounds. The lower limit of quantitation was 10 ng/ml for encainide and ODE and 15 ng/ml for MODE. This HPLC procedure represents a quick and reliable method of measuring encainide and its major metabolites in both urine and serum, making the assay applicable as an aid for therapeutic drug monitoring of patients receiving encainide therapy.