Disposition and metabolism of ralfinamide, a novel Na-channel blocker, in healthy male volunteers.

Ralfinamide is an α-aminoamide derivative with ion channel blocking properties, acting both peripherally and centrally through different molecular targets important in pain control. Absorption, blood and plasma time courses, and urinary and faecal excretion of total radioactivity were assessed in 6 male healthy volunteers administered a single oral dose of 320 mg ¹4C-(S)-ralfinamide. Pharmacokinetics of the parent drug were investigated over 120 h, urinary and plasma metabolites up to 192 h post-dose. ¹4C-(S)-ralfinamide was rapidly and completely absorbed. Ralfinamide and the dealkylated ralfinamide metabolite (NW-1716) represented the majority of plasma radioactivity. Plasma elimination of the parent compound occurred mono-exponentially (half-life approx. 15 h). ¹4C-radioactivity was eliminated in a bi-phasic manner (terminal half-life of 60 and 24 h for plasma and whole blood, respectively). Plasma-concentrations of unchanged ralfinamide were significantly lower than radioactivity concentrations, indicating metabolism of the parent compound. At 192 h post-dose the total balance of radioactivity was almost complete (95%). The main route of excretion was via the kidneys (94% of the dose). Major metabolites identified in urine and plasma were the N-dealkylated acid of ralfinamide and deaminated ralfinamide acid (NW-1799). Other metabolites, in particular the product of glucuronide conjugation N-dealkylated-ß-glucuronide, were identified.

Absolute bioavailability and pharmacokinetics of avosentan in man.

OBJECTIVE: Avosentan is a potent, selective endothelin A receptor blocker. The pharmacokinetics of avosentan were investigated in healthy male and female volunteers, following oral and i.v. administration of single doses of avosentan and its absolute bioavailability was determined. METHODS: In a randomized, balanced open-label, three-period oral crossover study, 26 healthy subjects (19 males and 7 females) received Treatments A, B and C. Treatment A consisted of a single dose of a 25 mg film-coated tablet of avosentan, Treatment B of a single dose of a 50 mg film-coated tablet of avosentan and Treatment C of 10 mg avosentan in 20 ml solution for infusion for 20 minutes (10 mg avosentan in 20 ml phosphate buffer pH 9.0 containing 1% polysorbate 20). Plasma concentrations of avosentan and its hydroxymethyl metabolite Ro 68-5925 were measured by liquid chromatography-tandem mass spectrometry. RESULTS: The absolute bioavailability values (compared with i.v. infusion) for the 25 and 50 mg film-coated tablets were 81% and 72%, respectively. The extent of absorption, as measured by partial and total AUC, increased almost proportionally with the dose. The estimated proportionality coefficient for AUC0- yen was 1.12 (90% CI 1.06, 1.18). For the rate of absorption (Cmax) strict dose-proportionality was not demonstrated (proportionality coefficient 1.13 (90% CI 1.0, 1.28)). No relevant gender differences in the pharmacokinetic characteristics were evident after a single i.v. dose and at an oral dose of 25 mg, whereas after oral administration of 50 mg of avosentan differences were seen in Cmax and t1/2. CONCLUSION: The absolute bioavailability of avosentan film-coated tablets is high, i.e. 70 - 80%.

Influence of food intake on the pharmacokinetics of avosentan in man.

OBJECTIVE: Avosentan is a potent, selective endothelin A receptor blocker. The effect of food intake on the pharmacokinetics of avosentan was investigated in healthy volunteers. METHODS: In a randomized, open-label, 2-period oral crossover study, 12 healthy subjects (8 males and 4 females) received Treatments A and B. Treatment A consisted of a single dose of avosentan 50 mg after a high-fat, high-calorie breakfast. Treatment B consisted of a single dose of avosentan 50 mg administered in the fasted state. Plasma concentrations of avosentan and its hydroxymethyl metabolite Ro 68-5925 were measured by liquid chromatography-tandem mass spectrometry. RESULTS: The overall exposure to avosentan and its metabolite, as reflected by the area under the plasma concentration-time curve from time zero to infinity (AUC0-inf), was not affected by food intake. The ratios of least square means (90% confidence interval (CI)) of AUC0-inf for avosentan and Ro 68-5925 in the fed and fasted state were 1.06 (0.96, 1.17) and 1.05 (0.96, 1.15), respectively. The maximum plasma concentration (Cmax) of avosentan and its metabolite was increased by food intake, and their apparent terminal half-life (t1/2) was shortened. The ratios of least square means (90% CI) of pharmacokinetic parameters for avosentan and its metabolite in the fed and fasted state were Cmax 1.61 (1.37, 1.90) and 1.46 (1.27, 1.67), and t1/2; 0.80 (0.69, 0.92) and 0.61 (0.51, 0.74), respectively. Single oral doses of avosentan were well tolerated under fasted and fed conditions. CONCLUSION: Food intake does not influence the pharmacokinetics of avosentan to a clinically relevant extent.

Influence of avosentan (SPP3OI) on the pharmacokinetics of a second generation oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers.

BACKGROUND: Avosentan (SPP301) is a potent and highly selective ETA receptor blocker and is clinically investigated in diabetic nephropathy. This study was designed to evaluate whether avosentan influences the pharmacokinetics of steroid oral contraceptives. METHODS: During a run-in phase, 16 healthy females received an oral contraceptive containing ethinylestradiol 0.03 mg and levonorgestrel 0.15 mg for the first 21 days of a minimum of one menstrual cycle. In a subsequent double-blind, randomized two menstrual cycle crossover treatment phase, subjects received either avosentan 25 mg or placebo once daily concomitantly with the oral contraceptive. Serum ethinylestradiol and plasma levonorgestrel concentrations were measured on Days 14 and 15 of the two treatment periods for the evaluation of the 24-hour kinetic parameters, and an additional sample was collected on Day 21 to determine their trough concentrations. Serum progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels as well as plasma avosentan and Ro 68-5925 levels were determined on Days 13, 14, 15 and 21 of each cycle of the treatment phase. RESULTS: Avosentan had a statistically significant lowering effect of 9 - 15% on the ethinylestradiol serum concentration levels. The 90% confidence intervals of the pharmacokinetic parameters did not include 1 or exceeded the 0.8 - 1.25 acceptance range for lack of interaction. The plasma concentration-time curves and pharmacokinetic parameters of levonor-gestrel were not statistically different during concomitant treatment with either avosentan or placebo. Compared to placebo, avosentan lowered the serum concentrations of progesterone statistically significantly by about 8% and increased slightly the LH and FSH serum concentrations. Safety and tolerability patterns were comparable during avosentan and placebo administration. CONCLUSION: Because of the effect of avosentan on the concentration levels of ethinylestradiol and progesterone, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during avosentan treatment.

Pharmacokinetic interaction between ketoconazole and SPP301 in healthy volunteers.

BACKGROUND: SPP301 is a potent and highly selective ETA receptor blocker. The primary aim of the present study was to investigate the effect of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of SPP301. METHODS: In a randomized, open-label 2-period oral crossover study, 12 healthy male subjects received treatments A and B. Treatment A consisted of 200 mg ketoconazole once daily on Days 1 - 4 and concomitantly 5 mg SPP301 on Day 3. Treatment B consisted of 5 mg SPP301 administered alone. Plasma concentrations of SPP301 and its hydroxymethyl metabolite were measured by LC-MS/MS. RESULTS: Ketoconazole coadministration increased the systemic availability of SPP301 and its hydroxymethyl metabolite 3-fold and prolonged their half-lives by a factor of 2. The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of ketoconazole for SPP301 and its metabolite were C(max) (maximum plasma concentration) 1.22 (1.13, 1.32) and 1.2 (1.05, 1.37), AUC(0-infinity) (area under the plasma concentration-time curve from time zero to infinity) 3.16 (2.84, 3.51) and 3.14 (2.49, 3.70) and t1/2 (apparent terminal half-life) 2.21 (1.55, 2.87) and 2.00 (1.17, 2.84), i.e. an increase of systemic exposure by a factor of 3.2, with individual exposures increasing up to 5.9-fold. Single oral doses of SPP301 were well tolerated when administered alone or together with multiple doses of ketoconazole. CONCLUSION: In the presence of potent CYP3A4 inhibitors exposure of SPP301 may be increased up to 6-fold.

Pharmacokinetic interactions of the oral renin inhibitor aliskiren with lovastatin, atenolol, celecoxib and cimetidine.

OBJECTIVE: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study investigated the interaction profile of aliskiren, which is of clinical importance because hypertensive patients often require concomitant drug therapy for associated comorbidities. METHODS: Four separate studies investigated the pharmacokinetic interaction between single oral doses of aliskiren and lovastatin, atenolol, celecoxib or cimetidine, respectively. All studies involved healthy male volunteers aged 18-45 years. In 3 studies, subjects (n = 15 in each study) received single doses of aliskiren 150 mg alone, the test drug alone (lovastatin 40 mg, atenolol 100 mg or celecoxib 200 mg), or both drugs in combination, according to a 3-period crossover design. In the cimetidine study (n = 12), aliskiren 150 mg was administered alone or concomitantly with cimetidine 800 mg according to a two-period crossover design. Plasma concentrations of aliskiren and test drugs were determined by liquid chromatography and mass spectrometry methods. Pharmacokinetic parameters were derived from these data. RESULTS: Mean AUC and t1/2 for aliskiren were not significantly changed by lovastatin, atenolol or celecoxib (< 10% difference between treatments). Aliskiren mean Cmax was not affected by either lovastatin or atenolol, although a non-significant 36% increase was observed with celecoxib. Modest, non-significant increases in aliskiren systemic availability followed coadministration with cimetidine (aliskiren mean AUC, Cmax and t1/2 increased by 17%, 19% and 15%, respectively). Aliskiren coadministration had no significant effect on the disposition of lovastatin, atenolol or celecoxib. CONCLUSIONS: Overall, single doses of aliskiren showed no evidence of clinically important pharmacokinetic interactions with lovastatin, atenolol, celecoxib or cimetidine.

Multiple-dose pharmacokinetics, pharmacodynamics and tolerability of the oral ET(A) endothelin-receptor antagonist SPP301 in man.

BACKGROUND: SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ET(A) receptor. The multiple-dose pharmacokinetics, pharmacodynamics, safety and tolerability of SPP301 were investigated in healthy male subjects. METHODS: In an ascending-dose, double-blind, placebo-controlled trial doses of 5, 20, 40 and 60 mg SPP301 were given orally on Day 1 and, after a wash-out period of 48 hours, once daily for seven days. At regular intervals, blood pressure and pulse rate, plasma levels of ET-1, and of SPP301 and its hydroxymethyl metabolite as well as urinary excretion of the parent drug and its metabolite were determined. RESULTS: SPP301 was generally well-tolerated. With the higher doses asymptomatic and transient increases in liver transaminases were observed. No other clinically relevant effects of SPP301 on hematology, biochemistry or urinalysis parameters were observed. Vital signs, ECG parameters and physical examinations showed no time or treatment effect. The pharmacokinetics of SPP301 and its hydroxymethyl metabolite (Ro 68-5925) were linear up to 40 mg SPP301. Steady state was reached after 3-4 days. The apparent terminal half-life of SPP301 and the metabolite was in the range of 7-10 hours after single and repeated doses. At the 60 mg dose level plasma concentrations of SPP301 decreased from the first to the last day of oral treatment. The average decreases in Cmax and AUC were 33% and 37%, respectively. Cmax and AUC of the metabolite amounted to about 4-6% of the values for SPP301 under single and repeated-dose conditions. Urinary excretion of SPP301 and of its metabolite were below 0.1% and 5%, respectively. CONCLUSION: SPP301 is quite well-tolerated, pharmacokinetics are linear and time-independent up to 40 mg multiple doses. Steady state is reached after 3-4 days. Urinary excretion of the unchanged drug plays a minor role in the elimination process of SPP301. ET-1 plasma concentrations increased about 1.5-fold at 20 mg and all further doses.

Development and validation of a disease-specific questionnaire on the quality of life of patients with chronic venous insufficiency.

BACKGROUND: Recording of Quality of Life (QoL) is taking on increasing importance in medicine. Although QoL cannot be measured directly, numerous methods studies have demonstrated that important areas of QoL can be addressed by validated questionnaires. The present study was designed to examine a new disease-specific, German-language questionnaire, the Freiburger Questionnaire of QoL in venous diseases (FLQA), with respect to reliability, validity and patient acceptance-among patients with chronic venous insufficiency (CVI). PATIENTS AND METHODS: The FLQA consists of 83 items and differentiates between limitations in QoL in 7 scales: physical complaints, everyday life, social life, emotional status, therapy, satisfaction, occupation. Data were collected from 246 patients with CVI stage I (n = 107), II (n = 75) and III (venous ulcer, n = 64) in the Widmer classification. RESULTS: In the psychometric test, the majority of scales showed little or no top or bottom effect. The internal consistency of the scales was generally high (Cronbach's Alpha in all scales more than alpha = .70 and in 4 scales above alpha = .90). The convergent validity with the Nottingham Health Profile and the ALLTAG was high in several scales. The FLQA showed good discriminant validity and significantly differentiated between the clinical CVI stages in several areas of QoL. The change sensitivity during the course of therapy was also good. In a feasibility test, the acceptance values among patients were high with respect to ease of understanding and description of the QoL areas relevant to them. The mean time to fill out the questionnaire was 21 +/- 6 minutes. CONCLUSION: Overall, the FLQA appears suitable to reliably record characteristics of QoL in patients with CVI in both course and cross-sectional studies.

Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state.

A study was performed in ten patients, stabilized with oxcarbazepine monotherapy (450-750 mg bid) for two weeks minimum, to investigate the possibility of using saliva to monitor the oxcarbazepine therapy. Thirteen paired blood and saliva samples were taken over 24 h. The saliva samples were obtained after stimulation. The analysis performed on the data suggests a dose dependence for the relationship between plasma and saliva concentrations of the main active metabolite, 10, 11-dihydro-10-hydroxycarbamazepine (MHD), and the importance of the type of stimulation for the saliva's production. Therefore it would be preferable to use plasma concentrations to monitor oxcarbazepine therapy, if necessary.

The influence of food on the disposition of the antiepileptic oxcarbazepine and its major metabolites in healthy volunteers.

The effect of food on the pharmacokinetics of the antiepileptic oxcarbazepine (OXC) was investigated in healthy volunteers. Six healthy male volunteers were treated with single peroral doses of 600 mg of oxcarbazepine (Trileptal) after overnight fasting or a fat- and protein-rich breakfast. Mean (+/- SD) areas under the plasma concentration-time curves (AUC) of the major component in plasma, the active monohydroxy metabolite (MHD), which is responsible for the therapeutic effect in man, were 672 (25) mumol L-1 h when given to the fasted volunteers and 780 (31) mumol L-1 h (p = 0.042) when given after a substantial breakfast. Mean (+/- SD) maximum concentrations (Cmax) were 25.5 (4.8) mumol L-1 when given to the fasted volunteers and 31.4 (5.3) mumol L-1 (p = 0.025) when given after breakfast. Thus, the average AUC was increased by 16% and Cmax by 23% when oxcarbazepine was given with food. The times at which Cmax was reached (tmax) as well as the terminal half-lives were not influenced by concomitant intake of food. The tolerability was the same whether oxcarbazepine was given before or after food in healthy volunteers. The slight effect of food on the kinetics of oxcarbazepine should be of little therapeutic consequence.

Quantitative determination of CGP 53,437, a new HIV protease inhibitor, in plasma by high-performance liquid chromatography and fluorescence detection.

A specific and sensitive liquid chromatographic assay for CGP 53,437 (I), a potent HIV protease inhibitor, is described. The method is based on a deproteinization step, followed by a liquid-liquid extraction with diisopropyl ether. Then a deprotection step of the primary amine and derivatization using fluorescamine is performed. Chromatography is achieved by isocratic elution with a mobile phase of 63 mM borax buffer (pH 9)-acetonitrile (58:42, v/v). The flow-rate of the mobile phase is 1 ml/min. The derivatives of compound I and its internal standard CGP 54,451, II, fluoresce at 480 nm on excitation at 395 nm. The limit of quantitation which is the lowest concentration of the analyte that can be measured with a coefficient of variation and a deviation from theory of less than 20%, was 5 nmol/l plasma. The analyte is stable for at least seven months in spiked human plasma samples. It is also stable after freezing and thawing cycles. Different human plasma sources and plasma samples from three different species (dog, marmoset, and rat) were tested and no interferences from plasma constituents was observed.

Clinical pharmacology and pharmacokinetics of oxcarbazepine.

Oxcarbazepine (OCBZ) is a new antiepileptic drug (AED) structurally related to carbamazepine (CBZ) but differing in several important aspects, notably metabolism and induction of metabolic pathways. Consequently, OXCB has fewer drug-drug interactions compared with CBZ. Absorption of OCBZ is rapid and complete. In animals it is responsible for the pharmacological effect. In humans, however, the parent compound is rapidly and extensively metabolized to a monohydroxy derivative (MHD), which is responsible for the therapeutic effect. Exposure to the MHD increases dose proportionally, and steady state is achieved after only three or four doses in a twice-daily regimen. When given with food, systemic exposure to MHD increases by about 17%. MHD is eliminated with a half-life of about 8-10 h. About 27% of the dose is recovered in the urine as unchanged MHD and a further 49% as a glucuronide conjugate of MHD. Results suggest that the kinetics of OCBZ should not be affected by impaired liver function. Impaired kidney function does not affect the kinetics of MHD; the glucuronide conjugate will, however, accumulate in these patients. The conversion of OCBZ to MHD is catalyzed by reductase enzymes, which are not subject to induction. Furthermore, OCBZ itself does not appear to induce the cytochrome P-450 family in general, although it does induce the P-450 IIIA subfamily, which is responsible for the metabolism of estrogens and the dihydropyridine calcium-channel blockers (e.g., nifedipine, felodipine). In patients, linear and dose-proportional kinetics with no autoinduction of metabolism simplify OCBZ dosage adjustment.

Influence of food on the disposition of the monoamine oxidase-A inhibitor brofaromine in healthy volunteers.

The effect of food on the bioavailability of brofaromine hydrochloride was investigated in a randomized cross-over study. Eight healthy male volunteers were given single peroral doses of 75 mg brofaromine hydrochloride after overnight fasting or a fat- and protein-rich breakfast. Mean (+/- SD) areas under the plasma concentration-time curves (AUC) were 9.66 (2.35) mumol l-1 h when given to the fasted volunteers and 11.82 (3.78) mumol l-1 h (p = 0.0413) when given after a substantial breakfast. Mean (+/- SD) maximum plasma concentrations (Cmax) were 0.71 (0.13) mumol l-1 when given to the fasted volunteers and 0.85 (0.22) mumol l-1 (p > 0.05) when given after breakfast. Thus, both the average AUC and Cmax were increased by approximately 20 per cent when brofaromine hydrochloride was given with food. The times when Cmax was reached (tmax) as well as the elimination half-lives were not influenced by concomitant intake of food. The tolerability was the same whether brofaromine was given before or after food in healthy volunteers. The slight effect of food on the bioavailability of brofaromine should be of little therapeutic consequence because of the observed wide inter-subject variability of the plasma levels.

Pharmacokinetics and pharmacodynamics of benazepril hydrochloride in patients with major proteinuria.

We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o. The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients. Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42%. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients. In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.

Pharmacokinetics of the antidepressant levoprotiline after intravenous and peroral administration in healthy volunteers.

To investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two-way crossover study. Blood and urine samples were collected after each dose. Unchanged levoprotiline and the sum of unchanged and glucuronidated levoprotiline (= total levoprotiline) were determined by a specific gas chromatographic-mass spectro-metric method. Intravenous levoprotiline was rapidly and extensively distributed into extravascular sites of the body; the steady-state volume of distribution was 18.81 kg-1. The elimination of levoprotiline from blood was independent of the dosing route, the half-life being 18.8 h. Only 1.8 and 0.6 per cent of the i.v. and p.o. dose, respectively, were excreted unchanged in the urine, whereas 57 per cent of each dose were renally excreted as total levoprotiline. The absolute bioavailability of p.o. levoprotiline was 40 per cent. About 60 per cent of the dose was subject to a first-pass effect in the liver. The systemic blood clearance of levoprotiline, determined after i.v. dosing, was 885 ml min-1, the renal blood clearance after i.v. and p.o. dosing was only 16.0 and 14.2 ml min-1, respectively. Presystemic and systemic clearance of levoprotiline occurred predominantly by direct glucuronidation.

Determination of the antidepressant levoprotiline and its N-desmethyl metabolite in biological fluids by gas chromatography/mass spectrometry.

A specific and sensitive gas chromatographic/mass spectrometric method was developed and validated for the determination of the antidepressant levoprotiline in blood, plasma and urine and the simultaneous determination of levoprotiline and its desmethyl metabolite in urine. Deuterium-labelled analogues were used as internal standards. The compounds were isolated from the biological fluids by liquid-liquid extraction under basic conditions. Following derivatization with perfluoropropionic anhydride, the samples were analysed by capillary column gas chromatography/electron impact mass spectrometry with selected ion monitoring. The analysis of spiked samples demonstrated the high accuracy and precision of the method. Blood concentrations of levoprotiline down to 0.7 nmol l-1 (1 ml used for analysis) could be quantified with a coefficient of variation of 10% or less. The method is suitable for use in pharmacokinetic and bioavailability studies of levoprotiline in humans.

Pharmacokinetics and pharmacodynamics of the ace inhibitor benazepril hydrochloride in the elderly.

The pharmacokinetics and pharmacodynamics of a single oral dose benazepril.HCl 10 mg have been studied in 15 healthy volunteers aged 65 to 80 y. The kinetics of unchanged benazepril and its active metabolite benazeprilat did not differ significantly in males and females, so the combined kinetic data from all 15 elderly subjects were compared with a historical control group of 19-32 year-old healthy men treated in the same way. The disposition of benazepril was not affected by age. The time to maximum plasma concentration, tmax (0.5 h) and elimination half-life (0.6 h) in the elderly were the same as in young subjects. The kinetics of benazeprilat was slightly changed in the elderly; although its tmax (1.5 h) was not affected, Cmax and the AUC were 20-40% greater. The elimination half-life of benazeprilat during the first 24 h after dosing in the elderly was increased by about 20% to 3.2 h. The renal plasma clearance of benazeprilat (18.1 ml.min-1) was about 20% smaller than in the young subjects. An average of 18.5% of the dose was recovered as benazeprilat in the 24 h urine from the elderly subjects, which was similar to the recovery in the young subjects. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 95%, respectively). Mean systolic and diastolic blood pressures in the elderly were reduced by a maximum of 37/16 mm Hg at 6 h, in association with a small rise in pulse rate. Treatment was generally well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of the angiotensin converting enzyme inhibitor benazepril.HCl (CGS 14 824 A) in healthy volunteers after single and repeated administration.

The pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril.HCl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10 mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once-daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril.HCl was rapidly absorbed (tmax = 0.5 h) and rapidly eliminated from plasma (t1/2 = 0.6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax = 1.5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t 1/2 = 2.7 h), whereas the terminal phase (t1/2 = 22.3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24-h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1.20 for AUC and 1.24 for urinary excretion. The effective half-life for accumulation was estimated at about 10-11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.

Pharmacokinetics of diclofenac and five metabolites after single doses in healthy volunteers and after repeated doses in patients.

1. The kinetics of diclofenac (I) and five of its metabolites (II-VI) were investigated in three healthy volunteers and in six patients. Compounds I-VI were measured by capillary column gas chromatography in plasma and urine. 2. After a single 100 mg dose of diclofenac sodium to volunteers, the drug was absorbed rapidly and showed peak plasma levels of 10-12 nmol/g. The maximum concentrations of five metabolites were comparatively low (0.36-2.94 nmol/g). The mono- and dihydroxy metabolites (II-V) had apparent terminal half-lives similar to that of I (1-3 h), but the hydroxymethoxy metabolite (VI) had a half-life of about 80 h. Renal elimination of VI within 96 h was about 1% of dose and that of I-VI was 36% (free plus conjugated). 3. Following daily treatment with 2 x 75 mg of an experimental sustained release formulation to patients for 6-10 months, steady-state trough concentrations of I-V in plasma were low (average values: 0.23-0.57 nmol/g). The mean trough concentration of VI was comparatively higher at 3.69 +/- 0.91 nmol/g presumably reflecting its accumulation. Despite this it is unlikely to contribute to the drug's therapeutic activity, since it has been shown in laboratory tests to be devoid of anti-inflammatory activity.

Determination of a new angiotensin converting enzyme inhibitor and its active metabolite in plasma and urine by gas chromatography-mass spectrometry.

A specific and sensitive gas chromatographic-mass spectrometric method for the simultaneous quantification of unchanged 3-[( 1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1- 1-(3S)-benzazepine-1-acetic acid (I) and its active metabolite, the dicarboxylic acid (II), in plasma and urine has been developed and validated. 2H5-labelled analogues of I and II were used as internal standards. The compounds were isolated from plasma and urine under acidic conditions using XAD-2 resin or Extrelut 1 columns. Following derivatization with diazomethane, the samples were analysed by packed-column gas chromatography-electron-impact mass spectrometry with selected-ion monitoring. The analysis of spiked plasma and urine samples demonstrated the good accuracy and precision of the method, which is suitable for use in pharmacokinetic and bioavailability studies with the new angiotensin converting enzyme inhibitor prodrug I.HCl in humans.