The effect of food on pharmacokinetics and pharmacodynamics of fenoldopam in class III heart failure.

Eighteen patients with New York Heart Association class III congestive heart failure were given single 100 mg oral doses of fenoldopam with food or fasting in a random-order single-blind crossover trial. Before and after each fenoldopam dose, thermodilution cardiac output, right atrial pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP) were measured with a balloon-tipped pulmonary artery catheter, and heart rates and blood pressures were recorded with an automated sphygmomanometer. Compared with fasting, bioavailability of fenoldopam was decreased significantly when administered with food: mean peak plasma fenoldopam level decreased from 26.5 (+/- 4.1 SEM) ng/ml to 10.9 (+/- 1.7 SEM) ng/ml (p = 0.0004) and mean area under the concentration-time curve was decreased from 44.7 (+/- 5.8 SEM) ng.hr/ml to 26.8 (+/- 4.1 SEM) ng.hr/ml (p = 0.0001). Fenoldopam administration to fasting patients resulted in decreases in mean arterial pressure, systemic vascular resistance, and PCWP and significant increases in cardiac index without change in heart rate. The maximum changes in mean cardiac index, systemic vascular resistance, and PCWP were greatest 1 hour after oral administration and did not persist beyond 3 hours after administration. In fasting patients, changes in cardiac index were correlated with plasma fenoldopam levels, whereas changes in PCWP and mean arterial pressure did not correlate significantly with the observed fenoldopam level.

Comparison between carvedilol and captopril in rats with partial ablation-induced chronic renal failure.

1. The effect of the novel beta-adrenoceptor antagonist and vasodilator, carvedilol (SK&F 105517, approximately 70 mg kg-1 daily in the food), and captopril (approximately 38 mg kg-1 daily in the drinking fluid) on the progression of chronic renal failure in rats was studied. 2. Six weeks following partial renal ablation, the urinary protein excretion of the carvediol- (60 +/- 21 mg day-1) and captopril-treated (35 +/- 9 mg day-1) animals was less than 50% that of control rats (133 +/- 27 mg d-1). 3. Serum creatinine (Scr) and urea nitrogen (SUN) concentrations of the carvedilol-(Scr, 0.63 +/- 0.09 mg dl-1; SUN, 11.3 +/- 1.2 mg dl-1) and captopril-treated (Scr, 0.82 +/- 0.05 mg dl-1; SUN, 14.1 +/- 1.5 mg dl-1) animals were also significantly (P < 0.05) lower than that observed in control animals (Scr, 1.4 +/- 0.3 mg dl-1; SUN, 19.2 +/- 3.9 mg dl-1), indicating that glomerular filtration rate was improved by both drugs. Plasma renin activity was significantly (P < 0.05) higher in captopril-treated rats (24.7 +/- 4.6 ng angiotensin I ml-1 h-1) than in either carvedilol-treated (7.9 +/- 1.4 ng angiotensin I ml-1 h-1) or control animals (7.4 +/- 1.0 ng angiotensin I ml-1 h-1). 4. Histological examination of the kidneys demonstrated a significantly reduced glomerular hypertrophy and glomerulosclerosis in those animals receiving carvedilol or captopril compared to controls. 5. Serum carvedilol concentration measured every 6 h for 24 h was variable and ranged on average from 57 +/- 13 ng ml-1 at 16 h 00 min to 121 +/- 31 ng ml-1 at 03 h 00 min. These data indicate that the rats probably had 24 h systemic exposure to carvedilol.6. The present study indicates that carvedilol is effective in attenuating the progression of chronic renal failure in rats.

Lack of a pharmacokinetic interaction at steady state between ropinirole and L-dopa in patients with Parkinson's disease.

STUDY OBJECTIVE: To assess the interaction between therapeutic dosages of ropinirole and L-dopa plus a decarboxylase inhibitor administered at steady state in patients with Parkinson's disease. DESIGN. Open, 6-week, overlap trial with random allocation. PATIENTS: Thirty patients with Parkinson's disease not previously treated with dopamine agonists, of whom 28 produced evaluable pharmacokinetic data for ropinirole and 23 for L-dopa. INTERVENTION: Group A (14 patients) received L-dopa for weeks 1-5 and ropinirole in increasing increments for weeks 2-6; group B (16) received ropinirole for weeks 1-5 and L-dopa for weeks 5 and 6. MEASUREMENTS AND MAIN RESULTS: Primary end points were AUC0-8 and Cmax for ropinirole, and AUC0-8, AUC0-infinity and Cmax for L-dopa. Secondary end points were Tmax for ropinirole, and Tmax and half-life for L-dopa. Coadministration with L-dopa at steady state did not affect rate or extent of availability of ropinirole: point estimates of the geometric mean ratio for ropinirole plus L-dopa compared with ropinirole alone for both Cmax and AUC0-8 approximated to unity. The small (16%) increase in peak concentrations of L-dopa on administration with ropinirole is unlikely to be of clinical consequence, as peak concentrations of L-dopa are typically highly variable. CONCLUSION: There are no pharmacokinetic grounds for adjusting dosages of either ropinirole or L-dopa when given in combination.

Simplified procedures for the determination of fenoldopam and its metabolites in human plasma by high-performance liquid chromatography with electrochemical detection: comparison of manual and robotic sample preparation methods.

Quantitative analytical methods, based on high-performance liquid chromatography with electrochemical detection, were developed for fenoldopam and its metabolites in human plasma. Two extraction methods, a liquid-liquid extraction method for fenoldopam and its methoxy metabolites and a liquid-solid extraction procedure for the sulfate and glucuronide conjugates of fenoldopam were developed. The extractions can either be performed manually or by robot. The limit of detection for fenoldopam, its sulfate and methoxy metabolites was 0.025, 2 and 0.5 ng/ml, respectively, at a signal to noise ratio of 4. The intra-assay and inter-assay coefficients of variation for both manual and robotic extraction procedures were comparable. These methods were suitably selective and sensitive for pharmacokinetic and metabolic studies of fenoldopam.

A retrospective analysis of fenoldopam renal excretion in 65 subjects: evidence for possible intrarenal formation of fenoldopam from its metabolites.

Clinical studies have suggested that the dopamine DA1 agonist, fenoldopam, may exhibit nonlinear renal excretion in humans. A retrospective population pharmacokinetic analysis of the renal excretion of fenoldopam and one of its major metabolites, fenoldopam-8-sulfate, was conducted in 65 healthy volunteers to examine this phenomenon. Fenoldopam-8-sulfate exhibited a mean (+/- SE) renal plasma clearance of 129 +/- 4 ml/min, which was independent of its AUC. In contrast, fenoldopam renal plasma clearance ranged from 2220 to 150 ml/min and decreased nonlinearily with increasing fenoldopam AUC. Fenoldopam renal clearance was characterized as a function of fenoldopam AUC using a nonlinear saturation model. The analysis predicted an initial maximal renal clearance of 2852 ml/min, which decreased to 78 ml/min at maximal inhibition. The fenoldopam AUC required to half-saturate fenoldopam renal clearance was 5.2 ng x hr/ml. The elevated clearance values for fenoldopam, beyond normal physiologic limits for renal blood flow in man, suggest that intrarenal formation of fenoldopam from one or more of its circulating metabolites may be contributing to the observed nonlinear decreases in fenoldopam renal excretion. Preliminary data from our laboratory suggest that in vivo desulfation of fenoldopam-8-sulfate to fenoldopam does occur in the dog.

Determination of SK&F 108566 (Teveten) in human plasma by reversed-phase high-performance liquid chromatography.

A sensitive, selective and rugged analytical method was developed for the determination of SK&F 108566 (eprosartan, Teveten) in human plasma. The new method employs a simple solid-phase extraction procedure to isolate the drug and its internal standard (SB-200062) from plasma samples. The assay is based on analysis by reversed-phase high-performance liquid chromatography with ultraviolet absorbance detection. The dynamic range of the assay is from 10.0 to 5000 ng/ml, based on 0.5-ml aliquots of plasma. No interference from the endogenous components of plasma, the anticoagulant, or sample collection devices have been noted. The assay has been fully validated. The mean within-run precision (6.5%), between-run precision (4.0%), accuracy (106%) and recovery (71.8%) of the method were considered acceptable. Additionally, SK&F 108566 was found to be stable in plasma under the storage and sample preparation conditions used. This assay has been successfully employed to provide pharmacokinetic data from clinical trials.

Determination of the enantiomers of fenoldopam in human plasma by reversed-phase high-performance liquid chromatography after chiral derivatization.

Fenoldopam, a selective agonist at peripheral dopaminergic (DA-1) receptors, is administered as a racemic mixture and, consequently, an indirect stereospecific high-performance liquid chromatographic assay was developed to study the disposition of the individual enantiomers in human subjects. Fenoldopam enantiomers were extracted from alkalinized plasma into ethyl acetate prior to precolumn derivatization with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). The resulting diastereomers were separated on a reversed-phase butylsilica column and determined using triple-electrode coulometric detection. The limits of determination and detection for the S- and R-enantiomers of fenoldopam were 0.5 and 0.25 ng/ml, respectively. A linear response was observed for (S)- and (R)-fenoldopam concentrations ranging from 0.5 to 50 ng/ml in plasma. The intra-day relative standard deviations (R.S.D.s) for the plasma assay at nominal concentrations of 0.5, 5 and 50 ng/ml were 17.4, 5.2 and 6.9%, respectively, for (S)-fenoldopam and 9.9, 6.2 and 7.4%, respectively, for (R)-fenoldopam. The inter-day R.S.D.s of the method at these concentrations were 9.3, 7.7 and 7.4%, respectively, for (S)-fenoldopam and 9.5, 1.9 and 7.3%, respectively, for (R)-fenoldopam. The mean accuracy of the method at concentrations of 0.5, 5 and 50 ng/ml in plasma was found to be 106.4, 111.8 and 108.9%, respectively, for (S)-fenoldopam and 116.2, 104.2 and 111.2%, respectively, for (R)-fenoldopam. The assay developed was sufficiently sensitive, accurate and precise to support pharmacokinetic studies in human subjects.

Pharmacology of SK&F R-105058 and R-106114, N-ethyl carbamate ester prodrugs of fenoldopam.

The pharmacology of SK&F R-105058 and SK&F R-106114, N-ethyl carbamate ester prodrugs of fenoldopam, was evaluated in pentobarbital-anesthetized dogs. The selective dopamine 1 (DA1) antagonist, SCH 23390, significantly attenuated the renal vasodilator effects of SK&F R-82526, the active enantiomer of fenoldopam. This dose of SCH 23390 also significantly attenuated the increase in renal blood flow and decrease in renal vascular resistance induced by the administration of either SK&F R-106114 or SK&F R-105058. The cholinesterase inhibitor, physostigmine, at a dose that significantly enhanced the renal effects of acetylcholine, did not alter the in vivo renal vasodilator effects of SK&F R-105058 or prevent conversion of SK&F R-105058 to fenoldopam. Thus, these data indicate that the renal vasodilator activity of fenoldopam prodrugs involves activation of DA1 receptors and that, unlike other carbamate ester prodrugs, conversion to the parent compound is unlikely to involve cholinesterase.

Continuous intragastric delivery of fenoldopam: relationship between plasma concentration and effects on renal function.

1. The pharmacodynamics of the dopamine DA1 agonist fenoldopam were examined in six healthy male volunteers after constant intragastric infusions of fenoldopam at dosages of 0, 10, 25, 50 and 75 mg h-1 for 6 h. 2. Hourly p-aminohippurate (PAH) clearance was used to assess fenoldopam induced renal plasma flow changes. Marked dose-related increases in renal plasma flow were noted with a maximal increase of 65% over baseline values of 711 ml min-1 being seen at the 75 mg h-1 rate. No changes in sodium excretion and glomerular filtration rate were observed. 3. Mean steady-state fenoldopam plasma concentrations were related to mean PAH clearance based on an Emax model (r = 0.996) with an Emax of 1350 ml min-1 and an EC50 of 6.2 ng ml-1. 4. Mean steady-state plasma concentrations of fenoldopam-7-sulphate and fenoldopam-8-sulphate failed to increase with dose but were linearly correlated to mean PAH changes (r = 0.998, r = 0.981 respectively). 5. These results support the concept of extending fenoldopam's duration of action through the development of an oral sustained delivery system.

Characterization of the renal effects and renal elimination of sulotroban in the dog.

The renal effects and renal handling of the nonprostanoid thromboxane receptor antagonist, sulotroban (4-[2-(phenylsulfonylamino)ethyl]phenoxyacetic acid), were characterized in dogs. Sulotroban was infused i.v. at 0.06, 0.2, 0.6 and 1.0 mg kg-1 min-1 (plus prime) for 180 min. Arterial blood pressure was reduced significantly during infusion of the 1.0 mg kg-1 min-1 dosage only. Diuresis, characterized by increases in both fractional and absolute urinary excretion of sodium, potassium, chloride and calcium, and decreases in urine osmolality occurred at each of the sulotroban dosages tested. The renal clearance of sulotroban exceeded the glomerular filtration rate, suggesting renal secretion of sulotroban. The transport maximum for sulotroban secretion was approximately 160 micrograms kg-1 min-1. Renal cortical slices from naive dogs accumulated [14C]sulotroban against a concentration gradient. Sulotroban accumulation was blocked by metabolic inhibitors (dinitrophenol and sodium azide) and inhibitors of organic anion transport (probenecid and p-aminohippurate), but not by inhibitors of organic cation transport (cyanine and tetraethylammonium), suggesting that tubular secretion of sulotroban is mediated by an organic anion transport system. It was concluded that: 1) decreases in blood pressure occurred only after high dosages and were associated with high plasma sulotroban concentrations; 2) diuresis occurred at all dosages and may represent a separate pharmacological action unrelated to thromboxane receptor antagonism; and 3) renal excretion of sulotroban in the dog occurs by both filtration and tubular secretion with secretion occurring via an organic acid transporter.

Identification of fenoldopam prodrugs with prolonged renal vasodilator activity.

Fenoldopam (SK&F 82526) is a short-acting selective dopamine-1 agonist in clinical trials for the treatment of hypertension, congestive heart failure and renal failure. In the present study, we tested various N-ethyl carbamate esters of fenoldopam in the conscious dog instrumented with a femoral arterial Vascular-Access-Port and a renal artery flow probe. Oral administration of SK&F R-82526 at 1 and 3 mumol/kg resulted in transient (30-60 min) dose-dependent increases in plasma fenoldopam levels and renal blood flow. Administration of the 7,8-bis-N-ethyl carbamate ester of R-fenoldopam (SK&F R-106114) and the 4',7,8-tris-N-ethyl carbamate ester of R-fenoldopam (SK&F R-105058) at 1, 3 and 10 mumol/kg p.o. also resulted in dose-dependent increases in plasma fenoldopam levels and renal blood flow; however, both parameters remained elevated for at least 4 hr. Intravenous administration of SK&F R-105058 also resulted in sustained plasma fenoldopam levels and increases in renal blood flow, indicating that slow absorption was not the cause of the sustained effect. The present study indicates that N-ethyl carbamate esters of fenoldopam are fenoldopam prodrugs which result in sustained increases in renal blood flow and plasma fenoldopam levels.