Etintidine-propranolol interaction study in humans

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC0-infinity values (573.5 vs. 146.4 ng.hr/ml, p = 0.0001) and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropranolol indicates that etintidine also increased the AUC0-24 values (43.8 vs. 16.4 ng.hr/ml, p = 0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.     

Etintidine-theophylline interaction study in humans

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of theophylline was investigated in 10 male volunteers. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of theophylline elixir (5 mg/kg) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 h following the administration of theophylline. Plasma theophylline levels were analysed by HPLC. Theophylline was rapidly absorbed following oral administration of the theophylline elixir to both the placebo and etintidine treatment groups. Comparison of the pharmacokinetic parameters of theophylline between the etintidine and the placebo groups indicates that while etintidine did not significantly (p greater than 0.05) affect the apparent Cmax (11.1 vs 10.0 micrograms ml-1) and Tmax (1.7 vs 1.4 h) values of theophylline, etintidine significantly reduced the oral clearance (0.0200 vs 0.0564 l kg-1 h-1, p = 0.000006) and prolonged the elimination half-life (16.8 vs 6.0 h) of theophylline. The data indicate that etintidine, like cimetidine, extended the elimination of theophylline in humans.     

Single-dose and multiple-dose pharmacokinetics of etintidine in healthy volunteers

Summary The present study was designed to determine the single- and multiple-dose pharmacokinetic profiles of the H₂ receptor antagonist etintidine in healthy volunteers.Etintidine was rapidly absorbed and eliminated after the oral administration of 300 mg base equivalent of etintidine HCl in a capsule formulation to 11 healthy subjects. Comparison of the pharmacokinetics after a single dose and during steady state showed no significant differences (p>0.05) in the mean values of C_max, t_max, oral clearance, elimination rate constant, and renal clearance, indicating no significant accumulation of etintidine and no apparent time-dependent changes in the pharmacokinetics of etintidine during multiple dose administration.     

Pharmacokinetics and bioavailability of etintidine in beagle dogs: Effects of routes of administration,doses, dosage forms,and chronic dosing

Etintidine HCl is an H₂ receptor antagonist which has been under clinical trial for the treatment of duodenal ulcer diseases. Our studies are to determine the effects of routes of administration, doses, dosage forms, and chronic dosing on the bioavailability and pharmacokinetics of etintidine (E) in the beagle dog. Salient findings are:

• 1 Plasma levels of etintidine after i.v. administration of 200mg of E followed a 3-exponential decay with a terminal t_½ of 1.7 h.
• 2 Following oral administration of 200mg of E in capsules, tablets, or a solution dosage form to dogs, etintidine was rapidly and nearly completely absorbed with no significant first-pass elimination.
• 3 A proportional increase in the amount of etintidine absorbed in the dogs occurred as the administered doses increased from 30 to 180 mg kg^?1 and this relationship did not change with repeated dosing.
• 4 Some accumulation of etintidine took place during the 52 weeks of chronic dosing.

     

Effects of a finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers

The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo. propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85–100°C, relative humidity 25–35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (C_max 41 vs. 28 ng·ml^–1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC_0–5h (119 vs 71 g·h·l_-1) of propranolol from 0 to 5 hours t_max, t_1/2 and AUC_0–24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase. The results suggest that a sauna may increase the plasma propranolol concentration, but that did not notably affect the blood pressure or heart rate in healthy, young volunteers during the post-sauna phase.     

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 methadone and its primary metabolite in 20 opiate addicts

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10–225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65–630 ng·ml^–1 and from 5 to 55 ng·ml^–1, whereas the peak concentrations were 124–1255 ng·ml^–1 and 10 – 301 ng·ml^–1 for methadone and EDDP, respectively. The calculated ratios between the area under the curve (AUC_{(0–24 h)}) for methadone and the AUC_{(0–24 h)} for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml·min^–1·kg^–1, whereas the mean elimination rate constant () and plasma half-life (t _1/2) were 0.026·h^–1 (range 0.013–0.053·h^–1) and 31.2 h (range 13–53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.     

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 sublingual and oral alprazolam in the post-prandial state

Summary We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study.The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes.Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography.Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P<0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml^–1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml^–1.Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h.In general the two routes were significantly different from placebo but not from each other.     

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.     

Effects of chlorpromazine on the disposition and beta-adrenergic blocking activity of propranolol in the dog

The effects of chlorpromazine (100mg p.o., 2hr before propranolol) on the disposition and beta-adrenergic blocking actions of both intravenous (6 mg) and oral (40 mg) propranolol were studied in the dog. Chlorpromazine pretreatment significantly reduced (69%) the oral clearance of propranolol, resulting in significant increases in propranolol bioavailability (159%), and in the total beta-adrenergic blocking activity (111%) after the oral dose. The increase in the total beta-adrenergic blocking activity of oral propranolol after chlorpromazine pretreatment was mostly due to an increased contribution from the parent compound; the apparent activity from active propranolol metabolites was not affected by chlorpromazine. Chlorpromazine pretreatment had no significant influence on the systemic clearance, elimination half-life, apparent volume of distribution, and plasma binding of propranolol, or on the apparent hepatic blood flow. After intravenous propranolol, chlorpromazine pretreatment had no effect on either the total amount of beta-adrenergic blocking activity or the amount of activity attributable to active metabolites. The decreased oral propranolol clearance by chlorpromazine was seen as a shift to the left in the propranolol dose vs. AUCrelationship, eliminating the apparent nonlinear kinetic behavior of oral propranolol, and reducing the apparent oral threshold dose. Chlorpromazine's major, if not only, effect on propranolol disposition was to reduce the presystemic elimination of propranolol, possibly through inhibition of its metabolism via a pathway other than ring oxidation.This work was supported by a US Public Health Grant No. HL-22718.     

Modulation of allergen-induced nasal symptoms and mediator release by treatment with N-acetyl-aspartyl-glutamate (ZY15106)

The aim of this study was to evaluate the effects of the new anti-allergic drug, N-acetyl-aspartyl-glutamate (ZY15106), on allergen-induced nasal symptoms and mediator release. Fifteen outpatients suffering from seasonal allergic rhinitis due to grass pollen were included in the study. A nasal antigen challenge followed by evaluation of symptoms was performed in basal conditions. Ten of the 15 patients underwent sequential nasal lavages in order to evaluate allergen-induced mediator release. The study was performed in winter, when the patients were symptom free, and was a randomized single-blind crossover trial of a 6 % solution of ZY15106 (daily dosage: 48 mg) versus placebo (lactose). The drug and the placebo were administered intranasally q.i.d. for 1 week, with a 2-week interval between the two treatments. Treatment with ZY15106, but not with placebo, caused a significant reduction in nasal obstruction in the first 30 min after challenge and at 60 min and itching in the first 10 min after challenge, but did not reduce sneezing and rhinorrhoea. Moreover, ZY15106 significantly reduced the histamine release in 5 min postchallenge lavage (4.5 ng·ml^–1 after placebo administration vs 2.5 ng·ml^–1, after treatment with ZY15106). A reduction in immunoreactive LTC₄ release in the 5 and 10 min post-challenge lavages was observed after ZY15106 administration (placebo vs active treatment: at 5 min 2.9 ng·ml^–1 vs 1.4 ng·ml^–1; at 10 min: 2.25 ng·ml^–1 vs 0.9 ng·ml^–1). These results indicate that 1-week treatment with ZY15106 can reduce antigen-induced nasal obstruction and itching, and mediator release in human nasal airways. The clinical activity of ZY15106 in the treatment of allergic rhinitis may be related to its ability to inhibit mediator release.     

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.     

Single-Dose Pharmacokinetics of Rifapentine in Women

Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (C_max ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 )] was 325 g · hr ml and the mean elimination half-life (t_1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t_1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.     

Interactions of the histamine H2-receptor antagonist etintidine with rat liver cytochrome P-450: a comparison with cimetidine

Summary The two imidazole histamine H₂-receptor antagonists etintidine and cimetidine interact with the rat liver microsomal cytochrome P-450. From type II spectral changes follows that the affinity of rat liver microsomal preparations for etintidine is about 5 times as high as for cimetidine when comparing both high and low affinity binding sites. After pretreatment with phenobarbital etintidine inhibited benzphetamine N-demethylation competitively (app. K _i: 4.0 mmol/l). Cimetidine inhibited benzphetamine N-demethylation in the same range. After pretreatment with phenobarbital both drugs inhibited the oxidation of benzo(a)pyrene for which etintidine showed a higher inhibitory potency than cimetidine. However, this oxidation could not be inhibited when microsomes of 5,6-benzoflavone pretreated rats were used. After pretreatment with 5,6-benzoflavone only etintidine but not cimetidine inhibited the O-deethylation of ethoxyresorufin competitively (app. K _i: 0.2 mmol/l). Etintidine and cimetidine were metabolized by rat liver microsomes to their corresponding sulphoxides. In conclusion, etintidine may cause mainly the same drug interactions as cimetidine but seems to be a more potent inhibitor.Parts of the results were presented on the spring meeting of the German Pharmacological Society, Mainz 1986, Federal Republic of GermanyThis work forms part of the doctoral thesis of M. Schulz Send offprint requests to A. Schmoldt     

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.     

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.     

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.     

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.     

Dose Proportionality of Transdermal Nitroglycerin

The FDA Cooperative Efficacy Study of transdermal nitroglycerin utilized a combination of marketed products over a wide dose range. Unfortunately, plasma nitroglycerin concentrations were not determined. The current study was conducted to assess plasma nitrate concentrations after transdermal doses of 15, 30, 60, and 105 mg/24 hr employing the FDA Cooperative Study design. Plasma concentrations of nitroglycerin, 1,3-glyceryl dinitrate, and 1,2-glyceryl dinitrate were determined during the 24 hr of application and for 1 hr after transdermal system removal. Dose proportionality was assessed after normalizing the data by theoretical dose. For nitroglycerin, dose-normalized AUC_{(0_)} and C _max were higher for the 105 mg/24 hr dose than for the other doses. For the metabolites, 1,3-glyceryl dinitrate and 1,2-glyceryl dinitrate, there were no differences in dose-normalized AUC_{(0_)} and dose-normalized C _max between the dose levels. No differences were seen in T _max between the dose levels for all three species. Based on the dinitrate metabolites, dose proportionality was seen over the 15 to 105 mg/24 hr dose range. Nitroglycerin, however, was found to be linear only between 15 and 60 mg/24 hr.