Biomedical subjects

K C Lasseter

Publications and source records attributed to K C Lasseter.

At least 19 recordsLinked to original sources

PubMed2003

Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment.

OBJECTIVE: To assess the effect of chronic hepatic impairment on rosuvastatin disposition, pharmacodynamic activity and tolerability. METHODS: This was an open-label, non-randomised, parallel-group trial. Six subjects were enrolled in each of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment), Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the latter two strata were age, weight, race, sex and smoking history matched. All subjects were given rosuvastatin 10 mg for 14 days. RESULTS: In subjects with CP-A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0-24) and C(max) were similar to subjects with normal hepatic function (geometric mean values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B who had the highest CP scores (i.e. the highest degrees of hepatic impairment) had the highest AUC(0-24) (128 ng h/ml and 242 ng h/ml) and C(max) (23.4 ng/ml and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased in all strata, but the response was more variable in the CP-B group. Rosuvastatin was well tolerated, and the safety profile was similar in subjects with hepatic impairment and normal hepatic function. CONCLUSION: In most subjects with mild-to-moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin were similar to subjects with normal hepatic function (more extensive hepatic impairment may increase systemic exposure to rosuvastatin), and most had LDL-C reductions similar to subjects with normal hepatic function.

Adult↗

PubMed2002

Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet.

BACKGROUND: This study compared directly the renal effects of two selective cyclooxygenase (COX)-2 inhibitors (rofecoxib and celecoxib) with naproxen (dual COX-1/COX-2 inhibitor) and placebo in healthy elderly subjects on a sodium-replete diet. METHODS: A total of 67 elderly subjects stabilized in the clinic for weight and urinary sodium on a controlled 200-mEq sodium diet were randomized in a double-blind fashion to receive rofecoxib, 25 mg daily (n = 17); celecoxib, 200 mg twice daily (n = 17); naproxen, 500 mg twice daily (n = 17); or matching placebo (n = 16) for 28 days. Subjects were sequestered in the clinic for the first 14 treatment days on the controlled diet. RESULTS: Daily urinary sodium excretion during the first 72 hours of treatment (primary endpoint) significantly decreased in rofecoxib, celecoxib, and naproxen groups compared with baseline (P < or =.05). Rofecoxib and celecoxib decreases in urinary sodium excretion rates that were comparable with each other, on the basis of predefined boundaries (-39.5 versus -27.1 mEq/d, respectively) and to naproxen (-40.6, mEq/d). Rofecoxib, celecoxib, and naproxen increased mean systolic blood pressure to a similar degree (3.4, 4.3, and 3.1 mm Hg, respectively, versus -1.3 mm Hg for placebo) after 14 days of treatment; small changes also occurred in diastolic blood pressure (0.3, 0.8, and -0.4 mm Hg, respectively, versus -1.4 mm Hg for placebo). Changes from baseline in creatinine clearance, body weight, and urinary potassium excretion among active treatments were similar. After 28 days of treatment, findings were generally consistent with those at 14 days. No subject reported edema or discontinued treatment as the result of an adverse experience. CONCLUSION: In healthy elderly subjects on a sodium-replete diet, the COX-2 inhibitors rofecoxib and celecoxib did not differ from a nonselective nonsteroidal anti-inflammatory drug (naproxen), in influencing renal function as measured by urinary sodium excretion, systolic and diastolic blood pressure, creatinine clearance, or weight change.

Aged↗

PubMed2001

Omapatrilat versus lisinopril: efficacy and neurohormonal profile in salt-sensitive hypertensive patients.

Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (P=0.008), ambulatory systolic blood pressure (P=0.004), and ambulatory mean arterial pressure (P=0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (P<0.001) increased urinary excretion of atrial natriuretic peptide over 0- to 24-hour (3.8-fold) and 12- to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (P<0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.

Adult↗

PubMed2001

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants.

This open-label, randomized study evaluated the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) following the application of a contraceptive patch (1/week) for three cycles (3 weeks/cycle). Healthy women (n = 24) wore a 20-cm(2) patch (ORTHO EVRA/EVRA) on either their abdomen or buttock during blood sampling weeks and on any of four approved sites at other times. Serum was analyzed for NGMN and EE from samples taken during Week 1 of Cycle 1 and Weeks 1-3 of Cycle 3. Steady-state conditions were achieved during the three-cycle study. The patch delivered NGMN and EE at steady-state concentrations within their reference ranges throughout three cycles of treatment; reference ranges are based on studies with ORTHO-CYCLEN/Cilest. Steady-state serum concentrations and area under the curve from 0 to 168 h increased only slightly from Cycle 1, Week 1 to Cycle 3, Week 3 for NGMN and EE, indicating minimal accumulation. Treatment was well tolerated, and patch adhesion was excellent.

Administration, Cutaneous↗

PubMed2001

Interactions between simvastatin and troglitazone or pioglitazone in healthy subjects.

Two randomized, two-period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG-CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once-daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once-daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once-daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration-time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG-CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by approximately 30% for Cmax and approximately 40% for AUC), but time to reach Cmax (tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (approximately 25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG-CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug-metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.

Administration, Oral↗

PubMed2000

Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial.

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects. OBJECTIVE: To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients. DESIGN: A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study. SETTING: Clinical research units. PATIENTS: 75 patients 60 to 80 years of age. INTERVENTION: In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet MEASUREMENTS: Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values. RESULTS: Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 m/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced. CONCLUSIONS: The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.

Aged↗

PubMed2000

The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function.

AIMS: To assess whether hepatic impairment influences the pharmacokinetics of ziprasidone. METHODS: Thirty subjects with normal hepatic function or a primary diagnosis of clinically significant cirrhosis (Child-Pugh A or B) were enrolled into an open-label, multicentre, multiple-dose study. The subjects with chronic, stable hepatic impairment and the matched control subjects received ziprasidone 40 mg day(-1), given orally with food, as two divided daily doses for 4 days and a single 20 mg dose on the morning of day 5. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 5. Liver function was evaluated quantitatively using antipyrine. RESULTS: On day 1 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax) of ziprasidone between the two groups. On day 5 there were no statistically significant differences in the Cmax or tmax for ziprasidone between the two groups. The mean AUC(0,12 h) for ziprasidone was statistically significantly greater in the hepatically impaired subjects compared with the normal subjects (590 ng ml(-1) h vs. 467 ng ml(-1) h, P = 0. 042). However, the AUC(0,12 h) increased by only 26% in the cirrhotic group compared with the matched control group. The ziprasidone lambda(z) in the subjects with normal hepatic function was statistically significantly greater than that in the hepatically impaired subjects (P<0.001). There was no correlation between antipyrine lambda(z) and ziprasidone lambda(z) in the subjects with normal hepatic function or in those with hepatic impairment. CONCLUSIONS: The findings of this study indicate that mild to moderate hepatic impairment does not result in clinically significant alteration of ziprasidone pharmacokinetics.

Adolescent↗

PubMed2000

Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug-drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug-drug interactions. OBJECTIVE: To determine the comparative effect of itraconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of cerivastatin, atorvastatin, and pravastatin. METHODS: In this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2)] were determined for parent statins and major metabolites. RESULTS: Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), Cmax, and t1/2 (27%, 25%, and 19%, respectively; P < .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P < .05 versus pravastatin alone), 24% (Cmax), and 23% (t1/2), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), Cmax (38%), and t1/2 (30%) (P < .05). The elevation in atorvastatin AUC was significantly greater than that of cerivastatin (P < .005) or pravastatin (P < .005). CONCLUSION: Itraconazole markedly elevated atorvastatin plasma levels (2.5-fold) after 20 mg dosing, suggesting that concomitant itraconazole/atorvastatin therapy be carefully considered. Itraconazole produced modest elevations in the plasma levels of cerivastatin 0.8 mg or pravastatin 40 mg (1.3-fold and 1.5-fold, respectively), indicating that combination treatment with itraconazole with cerivastatin or pravastatin may be preferable.

Adult↗

PubMed1999

Effective dose range of candesartan cilexetil for systemic hypertension. Candesartan Cilexetil Study Investigators.

The results of this randomized, double-blind, placebo-controlled, forced-dose titration study in a diverse population of hypertensive patients in the US indicate that candesartan cilexetil has clinically meaningful dose-related blood pressure-lowering effects and that maximum blood pressure reduction is achieved with doses of 16 and 32 mg given once daily. This study confirms that candesartan cilexetil is a highly effective antihypertensive agent with an excellent tolerability and safety profile, without dose-related adverse effects.

Antihypertensive Agents↗

PubMed1999

Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids.

Conventional nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase (Cox) isoforms (Cox-1 and Cox-2) and may be associated with nephrotoxicity. The present study was undertaken to assess the renal effects of the specific Cox-2 inhibitor, MK-966. Healthy older adults (n = 36) were admitted to a clinical research unit, placed on a fixed sodium intake, and randomized under double-blind conditions to receive the specific Cox-2 inhibitor, MK-966 (50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor, indomethacin (50 mg t.i.d.), or placebo for 2 weeks. All treatments were well tolerated. Both active regimens were associated with a transient but significant decline in urinary sodium excretion during the first 72 h of treatment. Blood pressure and body weight did not change significantly in any group. The glomerular filtration rate (GFR) was decreased by indomethacin but was not changed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1alpha was decreased by both MK-966 and indomethacin and was unchanged by placebo. Cox-2 may play a role in the systemic biosynthesis of prostacyclin in healthy humans. Selective inhibition of Cox-2 by MK-966 caused a clinically insignificant and transient retention of sodium, but no depression of GFR. Inhibition of both Cox isoforms by indomethacin caused transient sodium retention and a decline in GFR. Our data suggest that acute sodium retention by nonsteroidal anti-inflammatory drugs in healthy elderly subjects is mediated by the inhibition of Cox-2, whereas depression of GFR is due to inhibition of Cox-1.

6-Ketoprostaglandin F1 alpha↗

PubMed1998

Population pharmacokinetics and pharmacodynamics of pyridostigmine bromide for prophylaxis against nerve agents in humans.

This study was conducted to determine the pharmacokinetics and pharmacodynamics of pyridostigmine given as 30 mg of pyridostigmine bromide every 8 hours in healthy subjects. Plasma pyridostigmine concentration and red blood cell acetylcholinesterase activity were measured in blood samples collected during a 3-week period. Population analysis was performed using standard pharmacokinetic and pharmacodynamic models with the nonlinear mixed-effect modeling software (NONMEM). The pharmacokinetic model that best fit the pyridostigmine plasma levels was a two-compartment open model with first-order absorption, a lag time, and first-order elimination from the central compartment. The pharmacodynamic model that best fit red blood cell acetylcholinesterase activity was an inhibitory Emax model with an effect compartment linked to the central compartment. The results showed that the pharmacokinetics of pyridostigmine bromide are both gender and weight dependent. The pharmacodynamic effect does not lag significantly from the plasma concentration and returns to near normal within 8 hours. With the present dosage regimen of 30 mg every 8 hours, 30% of individuals may not have red blood cell acetylcholinesterase inhibition > 10% at the time of the trough.

Acetylcholinesterase↗

PubMed1998

Pharmacokinetics and pharmacodynamics of irbesartan in patients with hepatic cirrhosis.

The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single- and multiple-dose (7 consecutive days) administration to normotensive subjects in an open-label, multiple-dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half-life (t1/2), area under the plasma concentration-time curve (AUC), apparent oral clearance (Cl(t)/F), renal clearance (Cl(r)), and accumulation index (AI). Steady-state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild-to-moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

Administration, Oral↗

PubMed1998

Pharmacokinetics and pharmacodynamics of zolmitriptan in patients with mild to moderate hypertension: a double-blind, placebo-controlled study.

Zolmitriptan is a potent selective 5HT1B/1D receptor agonist for acute migraine therapy. Zolmitriptan has vasoconstrictor activity in cerebral vessels and may cause slight elevations of blood pressure in subjects without hypertension. Therefore, the pharmacokinetics and pharmacodynamics of zolmitriptan (5, 10, and 20 mg) were evaluated in 16 patients with mild to moderate hypertension (controlled by hydrochlorothiazide 50 mg once daily) and 17 healthy age- and sex-matched control subjects in a randomized, placebo-controlled, double-blind, four-period crossover study. The pharmacokinetics of zolmitriptan and its metabolites were dose proportional. Although area under the concentration-time curve (AUC0-infinity) and maximum concentration (Cmax) were slightly higher in patients with hypertension at all doses, this was only statistically significant for AUC at the 20-mg dose. Differences between subjects with and without hypertension were not clinically significant. Zolmitriptan produced a small increase in blood pressure, but this was similar in subjects with and without hypertension and was of no clinical significance. Zolmitriptan was well tolerated in both groups. Zolmitriptan plasma concentrations were higher in women than in men, with higher values of AUC and Cmax and lower total clearance in women. These results indicate that zolmitriptan can be administered for treatment of migraine in patients with controlled hypertension without dose adjustment.

Area Under Curve↗

PubMed1998

First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial.

WR 238605 is an 8-aminoquinoline drug currently under development for prophylaxis and treatment of malaria. Preclinical studies have demonstrated that it has greater efficacy and less toxicity compared with primaquine. In this first-time-in-human randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerance and pharmacokinetics, WR 238605 was administered to 48 men in single oral doses ranging from four to 600 mg (base). It was well tolerated, with gastrointestinal disturbances as possible side effects. Linear kinetics were demonstrated at these doses. WR 238605 has a long absorption phase and is slowly metabolized, with a tmax of 12 hr and an elimination half-life of 14 days. These safety, efficacy and pharmacokinetic properties make this drug an excellent candidate for further testing as a prophylactic, radical curative, and terminal eradication drug.

Adult↗

PubMed1997

Evaluation of indapamide 1.25 mg once daily in elderly patients with mild to moderate hypertension.

The objective of this study was to evaluate the safety and efficacy of indapamide 1.25 mg once daily as monotherapy in elderly patients (65 years and older) with mild to moderate essential hypertension. Two hundred and seventy-nine (279) elderly patients were enrolled in a washout period, during which patients received single-blind placebo for 4 weeks. Patients demonstrating supine diastolic pressures between 95 mm Hg and 114 mm Hg at the end of the 4-week placebo washout period were entered into the 8-week double-blind treatment period. Two hundred and four (204) patients qualified for the study and were randomized to the double-blind treatment; 103 patients received indapamide 1.25 mg and 101 patients received placebo for 8 weeks. Overall, 177 patients (92 indapamide and 85 placebo) completed the study. The primary efficacy criterion was the mean change in supine diastolic blood pressure (DBP) from double-blind baseline to the end of 8 weeks of therapy. By week 8 of the double-blind treatment period, indapamide 1.25 mg produced a statistically significant (P = 0.0037) decrease in supine DBP of 8.2 mm Hg compared to a decrease of 5.3 mm Hg produced in the placebo group. Additionally, indapamide 1.25 mg was statistically (P = 0.0028) more effective than placebo in reducing supine systolic BP (SBP) (-10.1 vs -4.2 mm Hg). The incidence of drug-related adverse events during the double-blind treatment period was similar between the two treatment groups. A low dose of indapamide, 1.25 mg, given once daily for 8 weeks was effective as monotherapy with respect to BP reduction in an elderly population with mild to moderate hypertension. Indapamide 1.25 mg was safe and generally well tolerated in this elderly patient population.

Aged↗

PubMed1997

Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile.

Montelukast sodium [1-([(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio]methyl)cyclopropylacetic acid sodium salt] (MK-476, Singulair) is a potent and selective antagonist of the cysteinyl leukotriene (Cys-LT1) receptor and is under investigation for the treatment of bronchial asthma. To assess the metabolism and excretion of montelukast, six healthy subjects received single oral doses of 102 mg of [14C]montelukast, and the urine and feces were collected. Most of the radioactivity was recovered in feces, with </=0.2% appearing in urine. Based on these results and the reported modestly high oral bioavailability of montelukast, it could be concluded that a major part of the radioactivity was excreted via bile. A second clinical study was conducted to identify biliary metabolites of montelukast. The bile was aspirated using a modified procedure involving a nasogastric tube placed fluoroscopically near the ampulla of Vater, after an oral dose of 54.8 mg of [14C]montelukast. This technique appears to be a new application for drug metabolism studies. The study was conducted with fasted and nonfasted subjects, with the bile being aspirated continuously under suction over periods of 2-8 hr and 8-12 hr after the dose, respectively. Two hours before the end of the collection procedure, cholecystokinin carboxyl-terminal octapeptide was administered iv to stimulate gallbladder contraction. Plasma samples also were collected periodically over 10 hr. Due to the nature of the collection procedure and the limited sampling time, recovery of radioactivity in bile was incomplete and varied from 3 to 20% of the dose. Radiochromatographic and LC-MS/MS analyses of bile showed the presence of one major and several minor metabolites, along with small amounts of unchanged parent drug. The minor metabolites were identified, by LC-MS/MS comparison with synthetic standards or by NMR, as acyl glucuronide (M1), sulfoxide (M2), 25-hydroxy (a phenol, M3), 21-hydroxy (diastereomers of a benzylic alcohol, M5a and M5b), and 36-hydroxy (diastereomers of a methyl alcohol, M6a and M6b) analogs of montelukast. The major metabolite was characterized as a dicarboxylic acid (M4), a product of further oxidation of the hydroxymethyl metabolite M6. Chiral LC-MS/MS analyses of M4 revealed that this diacid, like M5 and M6, was formed in both diastereomeric forms. The levels of metabolites in the systemic circulation were low in the fed as well as fasted subjects, with <2% of the circulating radioactivity being due to metabolites M5a, M5b, M6a, and M6b. Overall, this bile aspiration technique, which is less invasive than either T-tube drainage or fine-needle percutaneous puncture, provided a convenient and expedient means of identifying the biliary metabolites of montelukast, relatively free of contributions from colonic microflora.

Acetates↗

PubMed1996

Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men.

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.

Adult↗

PubMed1995

Single-dose and steady-state pharmacokinetics of fosinopril and fosinoprilat in patients with hepatic impairment.

The single-dose and steady-state pharmacokinetics of the angiotensin-converting enzyme (ACE) inhibitor fosinopril and its active diacid, fosinoprilat, were evaluated in 6 healthy volunteers and 12 patients with alcoholic cirrhosis. Fosinopril was administered at a dosage of 10 mg once daily for 14 days. Results in the two groups were similar, with no evidence of accumulation of fosinoprilat in hepatically impaired patients. Mean (+/- SD) maximum observed plasma concentrations of fosinoprilat in the healthy subjects were 112.0 +/- 67.2 ng/mL after the first dose and 144.1 +/- 61.7 ng/mL at steady-state. Corresponding values for the hepatically impaired patients were 111.4 +/- 40.1 ng/mL and 140.2 +/- 50.9 ng/mL. The area under the serum concentration versus time curve for healthy volunteers was 790.7 +/- 431.0 ng.hr/mL after the first dose and 940.3 +/- 400.4 ng.hr/mL at steady-state. Similar values were noted in hepatically impaired patients: 926.0 +/- 293.9 ng.hr/mL and 1,255.4 +/- 434.0 ng.hr/mL for first dose and steady-state, respectively. No statistically significant differences were detected in fosinoprilat pharmacokinetic values between healthy and hepatically impaired subjects. Absence of accumulation can be attributed to the dual route of elimination of fosinoprilat reported in previous studies. Renal excretion of fosinoprilat in hepatically impaired patients prevents increased accumulation. The present findings suggest that the starting dose of fosinopril used in hypertensive patients with normal renal and hepatic function can also be used in patients with hepatic impairment secondary to cirrhosis.

Antihypertensive Agents↗