Studies on hydralazine

Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline^®), the serum half-life (T1/2) and bioavailability (AUC_0–) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC_0– was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml^–1, compared to 0.66±0.12 µg·hour·ml^–1 in the fast acetylators (p<0.025). Treatment with Apresoline^® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml^–1 and 33.4±4.2 ng·ml^–1 in 8 slow and 5 fast acetylators, respectively (p<0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml^–1 and 147.6±15.0 ng·ml^–1 in slow and fast acetylators, respectively (p<0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.     

Growth hormone-releasing activity of hexarelin in humans

Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH₂) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·g·kg^–1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (C_max) were 3.9, 26.9, 52.3, 55.0 ng·ml^–1 after 0, 0.5, 1 and 2 g·kg^–1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC_0–180) were 0.135, 1.412, 2.918 and 3.695 g·min·ml^–1. The theoretical maximum response (E_max) and the dose that produces half of the maximum response (ED₅₀) were estimated using logistic regression. The calculated ED₅₀ values were 0.50 and 0.64 g·kg^–1 for C_max and AUC_0–180, respectively. The corresponding E_maxs were 55.1 ng·ml^–1 and 3936 ng·min·ml^–1, thus indicating that the effect after the 2 g·kg^–1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.     

Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its ₁-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung ₁-and rat reticulocyte ₂-adrenoceptors.The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (C_max) of R,S-metoprolol after administration of the conventional formulation was 140 ng·ml^–1, (n=7) and it was approximately one-third of that after the sustained-release formulation, 49 ng·ml^–1, (n=6); the AUC_{0–24 h}-values for the formulations were 700 and 310 ng·h·ml^–1, respectively. The C_max for the ₁-adrenoceptor binding component of metoprolol was 180 ng·ml^–1 (n=7) after administration of the conventional, and 74 ng·ml^–1 after administration of the sustained-release formulation. The corresponding AUC_{0–24 h}-values for the receptor binding component were 920 and 470 ng·h·ml^–1 (n=7).Thus, the kinetic differences between R,S-metoprolol and the ₁-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage ₁- and ₂-adrenoceptor occupancy of metoprolol in plasma was 5–15% less than after administration of the conventional formulation. At 0.5–1.5 h after drug intake the average ₁-adrenoceptor occupancy of the conventional formulation varied between 80–90% and that of the sustained release formulation between 20–76%. At these times the differences in receptor occupancy were significant; at 0.5–2 h after drug intake the average ₂-adrenoceptor occupancy of the conventional formulation varied from 20–30%, and that of the sustained-release formulation was 2–17%. At other times the difference in receptor occupancy between the formulations was not significant.The results demonstrate that plasma concentration-kinetics were more discriminating than -adrenoceptor-binding in analysing bioequivalence. It was possible to determine the bioavailability of the active ingredient of metoprolol and to study pharmacodynamic bioequivalence by using receptor binding assays.     

The pharmacokinetics of amiloride-hydrochlorothiazide combination in the young and elderly

Summary The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics.The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml·min^–1, amiloride; and from 418 to 157 ml·min^–1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng·ml^–1, C_ss,max; from 2 to 8 ng·ml^–1, C_ss,min; and from 4 to 14 ng·ml^–1, C_av; Hydrochlorothiazide: from 184 to 651 ng·ml^–1, C_ss,max; from 31 to 121 ng·ml^–1, C_ss,min; and from 89 to 273 ng·ml^–1, C_av).The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r=0.62, young;r=0.72, elderly).As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination.     

A lack of pharmacokinetic interaction between ranitidine and piroxicam

Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects.In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (C_max) was 467 ng·ml^–1 for ranitidine alone and 466 ng·ml^–1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml^–1 and 2551 h·ng ml^–1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively.In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean C_max was 2.1 ·ml^–1 in the presence of placebo and 2.0 g·ml^–1 in the presence of ranitidine respectively; mean AUC was 133 h·g ml^–1 and 137 h·g ml^–1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.     

Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure

Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose.The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml^–1) and maximum plasma concentration (75.0 ng·ml^–1) were lower than in subjects with normal renal function (19300 ng·ml^–1; 122 ng·ml^–1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure.Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.     

The tolerability,pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability,in healthy volunteers

447C88 (N-Heptyl-N-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC₅₀ of 10.2 ng·ml^–1 (23 nM). It is poorly absorbed but 5 mg·kg^–1·day^–1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats.In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food.All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean C_max and AUC were 1.8 ng·ml^–1 and 9.0 ng·ml^–1·h after 200 mg rising to 5.4 ng·ml^–1 and 23.8 ng·ml^–1·h respectively after 800 mg; t_1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.     

Pharmacokinetics of oral salbutamol controlled-release in Asian patients with asthma

Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients.Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean C_max was 4.2 ng·ml^–1 and 7.7 ng·ml^–1 after 4 and 8 mg, respectively. In 5 patients the steady state mean C_max, C_min and t_max were 8.1 ng·ml^–1 and 4.7 ng·ml^–1 and 6 h for the 4 mg tablets and 14.1 ng·ml^–1 and 7.1 ng·ml^–1 and 4 h for the 8 mg tablets.It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.     

Interaction of talinolol and sulfasalazine in the human gastrointestinal tract

Summary The absorption of talinolol (TA) 50 mg was investigated without and together with the co-administration of sulfasalazine (SASP) 4 g in 11 healthy young volunteers, in order to clarify gastrointestinal transit of TA.Without SASP, the t_max of TA was 2.8 h, C_max was 112 ng·ml^–1 and the half life was 12 h; the AUC_o-t was 958 ng·ml^–1·h.In the case of concomitant administration of SASP, TA was found only in serum from 3 individuals, with a C_max of 23 ng·ml^–1 and a mean AUC_o-t of 84 ng·ml^–1·h. TA was not detectable in 5 subjects and it was at the limit of detection (2 ng·ml^–1) in 3 subjects. Pharmacokinetic analysis was not possible in any of those individuals.The reason for the interaction appears to be the adsorption of TA by SASP. An interval of 2–3 h should elapse between giving SASP and other drugs.     

Bronchoconstriction of the asthmatic airway by inhaled and ingested propranolol

Summary Responsiveness to inhaled histamine and DL propranolol hydrochloride was measured in 31 adult asthmatics and compared with bronchoconstriction provoked by acute oral propranolol dosing (max 160 mg).Twelve asthmatics developed 15% reduction in the forced expired volume in 1 s (FEV₁), 2 h after 100 mg oral propranolol; cardiac -adrenoceptor blockade was confirmed by cycle exercise tests in the 19 without airway response. The provocative inhaled dose of each aerosol causing a 20% fall in FEV₁ (PC₂₀) was lower, histamine 0.43 mg·ml^–1, propranolol 3.12 mg·ml^–1, in the 12 with a positive oral test compared with the 19 with a negative test, PC₂₀ histamine 1.65 mg·ml^–1, PC₂₀ propranolol 16.2 mg·ml^–1 (P < 0.001 for both aerosols). A correlation was demonstrated between the PC₂₀ values for asthmatics with a negative oral test (r=0.72, P < 0.001, n=19) but not for the remainder (r=0.14, P > 0.05, n=12).Plasma propranolol concentrations (CL, ng·ml^–1) after the final oral dose did not correlate with the % FEV₁(26.3) (r=-0.28) when an airway response was provoked or with the reduction in exercise tachycardia (25.9%) (r=0.31) when no bronchoconstriction occurred. CL exceeded the limit of detection after the final inhaled propranolol dose (7.5 ng·ml^–1) and was weakly related to the PC₂₀ propranolol value (r=0.53, P=0.01, n=27). The prevalence of a positive oral challenge was low in this group (39%). APC₂₀ propranolol value which was 100% sensitive as a predictor of a positive oral test had low specificity (58%) and a low predictive value (60%).This study has not found that nonspecific bronchial responsiveness to histamine or specific responsiveness to inhaled propranolol can be employed to predict bronchoconstriction in asthmatics following acute oral propranolol dosing.     

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients

Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous ¹⁴C-fosinoprilat (7.5 mg), oral ¹⁴C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study.Mean maximum concentration (C_max), clearance (CL), volume of distribution at steady-state (V_ss), mean residence time (MRT_iv), and t_1/2 values after IV administration of ¹⁴C-fosinoprilat were 2,042 g·ml^–1, 11.3 ml·min^–1, 11.01, 16.3 h and 28.3 h, respectively. Following oral administration of ¹⁴C-fosinopril, mean C_max, time to maximum plasma concentration (t_max), and fosinoprilat bioavailability values were 197 ng·ml^–1, 5.2 h and 29.2 %. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15 % and 2 % of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5 % of the administered dose. The maximum effect (E_max) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. E_max ranged from 95.3 to 102.5 %, and IC₅₀ (the fosinoprilat concentration required to produce 50 % of E_max) ranged from 2.6 to 4.2 ng·ml^–1.Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.Presented in part at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Antonio, TX, March, 1990     

Effect of entacapone,a COMT inhibitor,on the pharmacokinetics of levodopa and on cardiovascular responses in patients with Parkinson's disease

Summary In an open, randomised, cross-over study we investigated the effect of a single 200 mg oral dose of entacapone, a novel catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa/carbidopa, and on the cardiovascular responses (blood pressure and pulse rate variation to standard stimuli) in eight parkinsonian patients.Entacapone significantly increased the mean area under the plasma concentration curve (AUC) of levodopa by 46%, from 3620 to 5280 h·ng·ml^–1 and prolonged its elimination half-life (t_1/2el) from 1.5 h to 2.0 h. The mean AUC of 3,4-dihydroxyphenylacetic acid (DOPAC), the monoamine oxidase-dependent metabolite of levodopa, was significantly increased from 122 to 343 h·g·ml^–1 by entacapone. A small decrease in the AUC of homovanillic acid (HVA), the COMT dependent metabolite of levodopa, was observed (from 455 to 303 h·ng·ml^–1). Entacapone also decreased the excretion of HVA but not that of 3-methoxytyramine in the urine.Cardiovascular autonomic responses to sympathetic and parasympathetic stimuli were not changed by entacapone.We conclude that a single dose of entacapone moderately increases the AUC and prolongs the t_1/2el of levodopa in man and that that does not affect cardiovascular autonomic regulation.     

Comparison of the diuretic effect and absorption of a single dose of furosemide and free and the fixed combinations of furosemide and triamterene in healthy male adults

Summary The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F+T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men.A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC₄₈₀) F 2.58 g · h · ml^–1; F+T 2.46 g · h · ml^–1; FT 1.97 g · h · ml^–1. There was a significant reduction in the AUC₄₈₀ of plasma triameterene (F+T 204.9 g · h · l^–1; FT 130.2 g · h · l^–1). Sodium excretion after F+T and FT was more pronounced than after F (F+T 302 mmol; FT 311 mmol; F 259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F+T as well as after FT (F 121 mmol; F+T 104 mmol; FT 107 mmol).It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.     

Flumazenil kinetics in the elderly

Summary In an open design, randomised, two-way cross-over study, a single 2 mg i.v. dose and a single 30 mg oral dose of flumazenil were each administered to a group of healthy young (n=6) and elderly (n=12) volunteers (male: female 2/1). Plasma samples were collected at intervals and intact drug was assayed.Both the IV and oral doses of flumazenil were very well tolerated by both age groups and no severe or unexpected adverse effects were observed. The main complaints were dizziness and headache, mainly after oral dosing, probably due to the higher C_max and AUC following this route of administration. After 2 mg i. v. the disposition parameters in the two age groups (elderly/young) were very similar: volume of distribution (V_ss): 0.88/0.901·kg^–1; total body clearance (Cl_PL): 0.86/0.99 l·min^–1; terminal elimination half-life (t_1/2): 1.02/0.91 h. After the 30 mg oral dose the mean C_max of 87.6 ng·ml^–1 (elderly) and 78.4 ng·ml^–1 (young) were generally reached within 0.5 to 1 h. In 26% (elderly) and 23% (young), the absolute bioavailability of flumazenil was very similar.It is concluded that the absorption and disposition paramters of flumazenil were not significantly affected by aging.     

Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring

The effect of atropine-induced reductions in saliva flow rate on saliva phenytoin concentrations were evaluated in a randomised placebo-controlled crossover study in a group of epileptic patients stabilised on the drug.Pretreatment with atropine caused significant reductions in saliva flow rates during the first 4 h, compared to saline. The AUC_{0–4 h} for saliva flow rate was significantly reduced by atropine (245 g vs 327 g) and the saliva phenytoin AUC_{0–4 h} was significantly increased (5.6 g · ml^–1 · h vs 4.5 g · ml^–1 · h) without affecting plasma phenytoin concentrations. The saliva/plasma phenytoin AUC_{0–4 h} ratio was therefore significantly increased by atropine (0.15 vs 0.12). However, there was a poor correlation between saliva/plasma phenytoin concentration ratios and saliva flow rates for the two treatments in the individual patients (correlation coefficient ranged from 0.25 to 0.65).These findings demonstrate that saliva phenytoin concentrations are increased by reductions in saliva flow rate. Caution is therefore required when saliva phenytoin concentrations are used for therapeutic monitoring in the presence of factors which may affect saliva flow rate.     

Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients

Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction.The mean t_1/2, C_max, t_max, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng·ml^–1, 4.8 h, and 3.19 g·h·ml^–1, respectively. Values for 1 CAPD patient with liver dysfunction were t_1/2 of 65.4 h, C_max of 182 ng·ml^–1, t_max of 9 h, and AUC of 18.1 g·h·ml^–1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml·min^–1.Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.These studies were supported in part by the Bristol-Myers Squibb Pharmaceutical Research Institute and by NIH grant M01-RR00065     

Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min^–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min^–1, and an elimination rate constant of 0.0044 min^–1. The corresponding estimates after i.m. administration were 0.324 l·min^–1, 34.1 l, 0.035 min^–1, and 0.0018 min^–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml^–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml^–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min^–1, with an EC₅₀ of 176 ng·ml^–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min^–1, 250 ng·ml^–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml^–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min^–1.     

The effect of exercise on atropine pharmacokinetics

Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO₂ max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1.Ex prior to atropine (T2) significantly decreased the mean volume of distribution (V_z, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t_1/2, 4.2 vs 3.5 h), V_z (278 vs 1981), and clearance (CL, 763 vs 638 ml·min^–1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml^–1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml^–1). In T5, Ex significantly decreased the t_1/2 (3.4 h), V_z (182 l) and CL (575 ml·min^–1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min^–1), elimination rate constant (ke, 0.0012 vs 0.0015 min^–1), C_p (14 ng·ml^–1) and AUC (53.3 ng·h·ml^–1).These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.Portions of this work were presented at the annual meeting of The American Society for Pharmacology and Experimental Therapeutics, Montreal, Canada, October 1988The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the opinions of the Department of the Army or the Department of Defense.     

Sublingual captopril — a pharmacokinetic and pharmacodynamic evaluation

Summary In this study we compared the pharmacokinetics and pharmacodynamics of captopril after sublingual and peroral administration. Single 25 mg doses of captopril were administered sublingually and perorally on two different occasions in a randomised cross-over fashion to eight healthy volunteers aged 22–35 years. The kinetics of unchanged captopril, plasma renin activity (PRA), BP and heart rate were studied over three hours after both peroral and sublingual administration of captopril.Mean pharmacokinetic parameters for unchanged captopril after sublingual administration were: C_max, 234 ng·ml^–1; t_max, 45 min; AUC (0–3 h), 15.1 g·ml^–1. min. Mean pharmacokinetic parameters for unchanged captopril after peroral administration were: C_max, 228 ng·ml^–1; t_max, 75 min; AUC (0–3 h), 17.0 g·ml^–1. min. t_max was significantly shorter when captopril was administered sublingually; all other pharmacokinetic parameters were equivalent.The plasma captopril concentrations achieved post drug administration led to increases in PRA and reductions in BP. t_max for PRA was 86 min for sublingual captopril and 113 min for perorally administered drug. Peak PRA values were, however, not significantly different. BP, as expected, was not reduced dramatically in these healthy volunteer subjects, however, in systolic BP vs time profiles, BP was significantly lower after volunteers received sublingual captopril. Heart rate increased slightly after captopril administration; there were no differences between the two routes of administration. Administration of captopril sublingually, therefore led to a more rapid attainment of plasma captopril concentrations and had a more rapid onset of pharmacological effect when compared with peroral administration.     

Comparative pharmacokinetics of bismuth from ranitidine bismuth citrate (GR122311X), a novel anti-ulcerant and tripotassium dicitrato bismuthate (TDB)

GR122311X (ranitidine bismuth citrate, Glaxo Group Research Ltd.) is a salt of ranitidine with a complex of bismuth and citric acid which is being developed for the treatment of peptic ulceration. In this study, 4 groups of 12 healthy male subjects were dosed for 10 days with either GR122311X 500 mg bid (301 mg bismuth per day), GR122311X 1.0 g bid (602 mg bismuth per day), tripotassium dicitrato bismuthate (TDB, DeNoltab, Gist Brocades Ltd., Weybridge, England) 240 mg bid (431 mg bismuth per day) or placebo.After the last dose the geometric mean for C_max for 500 mg bid of GR122311X was 5 ng·g^–1, for 1.0 g bid GR122311X it was 12 ng·g^–1 and it was 21 ng·g^–1 for 240 mg TDB bid. The corresponding trough plasma levels were 2 ng·g^–1, 4 ng·g^–1 and 4 ng·g^–1, respectively.The AUC over a dosing interval after the last dose (AUC) were 34 ng·h·g^–1, 71 ng·h·g^–1 and 79 ng·h·g^–1, respectively. The bismuth urinary recoveries over the last dosing interval (Ae) were 97 g, 227 g and 309 g, respectively, which is less than 1 % of the administered doses. The renal clearance of bismuth was less than the glomerular filtration rate. After adjustment for bismuth dose, the C_max for GR122311X 500 mg was 35 % that of TDB, while for GR122311X 1.0 g the C_max was 42 % that of TDB. Similar differences were observed for Ae.In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Ae and C_max, with a much narrower C_max range than those observed for TDB.