Interspecies Pharmacokinetics of a Novel Hematoregulatory Peptide (SK&F 107647) in Rats,Dogs, and Oncologic Patients

Purpose. To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. Methods. Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 ng/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). Results. In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vd_ss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a·W^b), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vd_ss, and T_1/2 of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. Conclusions. Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.     

Pharmacokinetics of a Hematoregulatory Peptide (SK&F 107647) in Healthy Male Volunteers and in Patients with Colorectal or Pancreatic Adenocarcinoma Not Amenable to Standard Therapy

Purpose. To describe the pharmacokinetics of SK&F 107647, a synthetichematoregulatory peptide, in healthy volunteers and in patientswith adenocarcinoma.Methods. SK&F 107647 pharmacokinetics were evaluated in 2dose-escalation studies. Volunteers received SK&F 107647 as single15-minute iv infusion doses of 1, 10, 100, 500, and 1000 g/kg. Cancerpatients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1g/kg once daily for 10 days. Drug concentrations were quantified in plasmaand urine of healthy volunteers and on days 1 and 10 in plasma ofcancer patients receiving the two top dose levels.Results. In volunteers, mean clearance (CL) ranged from 76.7 to 101ml/hour/kg; mean volume of distribution at steady-state (V_ss)rangedfrom 175 to 268 ml/kg. Most of the administered dose was renallyexcreted as intact peptide within 24 hours postinfusion. In patients,mean CL was 57.6 ml/hour/kg, mean V_ss ranged from 128 to 150ml/kg and terminal half-life from 2.1 to 3.4 hours. There was littleaccumulation of drug. In both studies, linear pharmacokinetics wasobserved. Clearance approached normal glomerular filtration rate(GFR) in volunteers and correlated with creatinine clearance incancer patients.Conclusions. SK&F 107647 exhibits linear pharmacokinetics, a smallV_ss, and clearance, primarily renal, approaching normal GFR.     

Antihypertensive activity of the non-peptide angiotensin II receptor antagonist,SK&F 108566, in rats and dogs

Summary The antihypertensive activity of the nonpeptide angiotensin II receptor antagonist, SK&F 108566 (E) - - [[2 - butyl -1 - [(4 - carboxyphenyl)methyl] -1H -imidazol-5-yl]methylene]-2-thiophene propanoic acid, was examined in rats and dogs. SK&F 108566 produced dose-dependent decreases in blood pressure in renin-dependent hypertensive rats. At 10 mg/kg intraduodenally, mean arterial blood pressure fell from between 150–160 mm Hg to approximately 124 mm Hg. A sustained infusion of SK&F 108566 at 25 g/min intraduodenally normalized blood pressure during 3 days of infusion and for 18 h following cessation of the infusion. Evaluation of the systemic hemodynamic effects of SK&F 108566 in chronically instrumented renin-dependent hypertensive rats demonstrated that the antihypertensive effects of SK&F 108566 were accompanied by a significant increase in cardiac output with little change in stroke volume. In dogs made acutely hypertensive by an intravenous infusion of angiotensin 1, SK&F 108566 resulted in dose-dependent decreases in blood pressure. The antihypertensive activity of SK&F 108566 at 10 mg/kg p.o. was maintained for between 13–15 h, a similar duration of action as observed with enalapril (1 mg/kg, p.o.). Administration of DuP 753 (losartan) intravenously caused a small and short-lived fall in blood pressure in the angiotensin I-infused hypertensive dog. However, the active metabolite of losartan, EXP 3174, resulted in a response of longer duration. In dogs made hypertensive by placement of an ameroid constrictor on the left renal artery, SK&F 108566 (10 mg/kg, p.o.) or enalapril (1 mg/ kg, p.o.) resulted in antihypertensive responses of at least 12 h duration. The data indicate that SK&F 108566 is a long-acting antihypertensive agent in the rat and dog.Send offprint requests to D. P. Brocks at the above address     

Absorption and Disposition of a Selective Aldosterone Receptor Antagonist,Eplerenone, in the Dog

Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.     

Pharmacologic and pharmacokinetic profile of SK&F S-106203, a potent,orally active peptidoleukotriene receptor antagonist,in guinea-pig

In this report the pharmacologic and pharmacokinetic profile of the leukotriene receptor antagonist 3(S)-1(2-carboxyethyl)thio]-3-12-(8-phenyloctyl)phenyl] propanoic acid (SK&F S-106203) in guinea-pigs is described. In isolated guinea-pig tracheae SK&F S-106203 was a potent, competitive antagonist of leukotriene (LT) D₄-induced contractions (pA₂ = 7.6). SK&F S-106203 was also a potent antagonist of LTE₄-induced contractions (pK_B = 7.3), but had little effect on those elicited by LTC₄ (pK_B = 5.5). SK&F S-106203 (10 μM) had no effect on contractions produced by histamine, carbachol, KCI, U-44069, PGF_2α or PGD₂. In addition, SK&F S-106203 (10 μM) did not inhibit cyclic nucleotide phosphodiesterase (PDE) activity of several PDE isozymes. In guinea-pig lung membrane preparations, SK&F S-106203 was a potent antagonist of ³H-LTD₄ binding with a K_i = 19.4 ± 2.1 nM (n = 5). The pharmacokinetic profile of SK&F S-106203 was determined in unanesthetized guinea-pigs. Following an i.v. (bolus) dose (25 mg/kg), SK&F S-106203 disappeared from plasma in a biphasic fashion with half-lives of 0.1 h (50% of the area under the plasma concentration-time curve, AUC) and 11 h. The AUC obtained for SK&F S-106203 following i.v. administration was 87.3 ± 7.5 μg-h/ml. Following an oral dose of SK&F S-106203 (100 mg/kg), the maximal plasma concentration (C_max) and the time C_max was achieved (T_max were 21.62 ± 2.26 kg/ml and 4 ± 1 h, respectively; the AUC was 279.9 ± 41.8 μg-h/ml. Studies examining the effects of i.v. infusion of SK&F S-106203 revealed that marked inhibition of LTD₄-induced bronchospasm was produced with steady-state plasma levels of SK&F S-106203 < 1 μg/ml (< 2 μM). Oral (p.o.) pretreatment with 100 μmol/kg SK&F S-106203 for up to 24 h essentially abolished LTD₄-induced bronchospasm; this correlated with sustained plasma concentrations of > 2 μg/ml. The results indicate that in guinea-pig airways, SK&F S-106203 is a potent and selective LT receptor antagonist that is active via aerosol, oral and i.v. routes of administration. When given orally, SK&F S-106203 is highly bioavailable and has a very long duration of action which correlates with the pharmacokinetic profile of the compound. SK&F S-106203 may be useful therapy in asthma and other disorders in which the Us are thought to play a prominent pathophysiological role.     

Pharmacokinetics, metabolism, and disposition of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine (SK&F 86466) in rats and dogs

The pharmacokinetics and metabolism of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine (SK&F 86466) have been studied in rats and dogs. Using radiolabeled SK&F 86466, it was shown that the compound was completely absorbed from the gastrointestinal tract following oral administration. Most of the administered radioactivity (approximately 80%) was excreted in urine with the remainder excreted in feces via the bile. Very little of the parent compound was excreted unchanged in the urine. The major urinary metabolite, accounting for about 55% of the dose in rat and 35% in dog, was the N-oxide. N-Demethylation also occurs in both species, and in the rat approximately 20% of the dose is metabolized by this route. The plasma concentration vs. time curves following iv administration were analyzed using a two-compartment open model. The distribution phase half-life was 0.24 hr in the rat and 0.37 hr in the dog. In both species the terminal half-life was approximately 2 hr. The volume of distribution at steady state in the rat was 12.1 liters/kg and in the dog was 8.2 liters/kg. About 55% of the drug in plasma was bound to protein in both species so that the volume of distribution of the free drug was 27 liters/kg in the rat and 19 liters/kg in the dog. The clearance of SK&F 86466 from blood was very high in both the dog (56 ml/min/kg) and the rat (191 ml/min/kg). Since less than 1% of the compound was excreted unchanged in urine, the clearance was almost entirely metabolic.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stereoselective Pharmacokinetics and Pharmacodynamics of Propylisopropyl Acetamide,a CNS-Active Chiral Amide Analog of Valproic Acid

Purpose. The purpose of this study was to evaluate there existed stereoselective effects in the pharmacokinetics, anticonvulsant activity, microsomal epoxide hydrolase (mEH) inhibition, and teratogenicity of the two enantiomers of propylisopropyl acetamide (PID), a CNS-active chiral amide analogue of valproic acid. Methods. Racemic PID, as well as the individual enantiomers, were intravenously administered to six dogs in order to investigate the stereoselectivity in their pharmacokinetics. Anticonvulsant activity was evaluated in mice (ip) and rats (oral), mEH inhibition studies were performed in human liver microsomes, and teratogenicity was evaluated in an inbred susceptible mice strain. Results. Following intravenous administration to dogs of the individual enantiomers, (R)-PID had significantly lower clearance and longer half-life than (S)-PID, however, the volumes of distribution were similar. In contrast, following intravenous administration of racemic PID, both enantiomers had similar pharmacokinetic parameters. In rats (oral), (R)-PID had a significantly lower ED₅₀ in the maximal electroshock seizure test than (S)-PID; 16 and 25 mg/kg, respectively. PID enantiomers were non-teratogenic and did not demonstrate stereoselective mEH inhibition. Conclusions. (R)-PID demonstrated better anticonvulsant activity, lower clearance and a longer half-life compared to (S)-PID. When racemic PID was administered, the clearance of (S)-PID was significantly reduced, reflecting an enantiomer-enantiomer interaction.     

Dog liver N-methyltransferase: A drug-metabolizing enzyme

A non-specific N-methyltransferase was demonstrated in dog liver. This enzyme is different from other N-methylating systems, especially in terms of substrate and species specificity. The enzyme catalyzes the methylation of a variety of endogenous and exogenous amines; of the compounds studied, SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline) was found to be the best substrate. The enzyme utilized S-adenosylmethionine but not 5-methyltetrahydrofolate as a methyl donor, and it had a pH optimum at 8.0. Study of SK&F 64139 with the partially purified enzyme indicated that this dog liver N-methyltransferase had very low K_m and high V_max values for SK&F 64139. Methylation of SK&F 64139 was not observed with the monkey or rat liver enzyme preparation. This finding is in accordance with the fact that SK&F 64139 is methylated extensively in the dog, but not in other species. The ability of this enzyme to methylate a number of arylalkylamines suggests its possible importance in drug biotransformation.     

Pulmonary Bioavailability of a Phosphorothioate Oligonucleotide (CGP 64128A): Comparison with Other Delivery Routes

Purpose. Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents. Methods. The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses. Results. Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intra-peritoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (<2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively. Conclusions. Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.     

Kinetics and disposition of picumeterol in animals

1. The pharmacokinetics and disposition of picumeterol, a novel β₂ receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels.

2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1?h in the rat and about 2?h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration.

3. Following instillation of ¹⁴C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2?min. After 2?h perfusion, no metabolites were detected in the recirculation perfusate or lung.

4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and β-oxidation are important as routes of metabolism.

5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.     

SK&F 93574, a histamine H2-receptor antagonist, releases histamine in the dog

This study was designed to establish whether SK&F 93574 releases histamine in dogs. Three female beagle dogs each received single infusions (on separate days) of each of SK&F 93574 (2.5 mg kg-1), polyvinylpyrrolidone (PVP, 20 mg kg-1) and sterile saline. The treatments were given at 14 day intervals by rapid intravenous infusion at 0.5 mL kg-1 min-1 for 2 minutes. Dogs showed clinical signs of histamine release such as vasodilation, licking lips, head drooping and increased gut movement after treatment with the known histamine releaser PVP or the test compound SK&F 93574. These signs were of similar severity and duration for the two compounds. No such changes were observed when the dogs received vehicle alone. Treatment with PVP or SK&F 93574 also resulted in markedly elevated plasma histamine concentrations (greater than 10-fold increase over control). It is concluded that intravenous administration of SK&F 93574 to dogs is associated with histamine release.     

Effect of the dopamine beta-hydroxylase inhibitor, SK&F 102698, on blood pressure in the 1-kidney, 1-clip hypertensive dog.

The acute and chronic effects of a potent selective dopamine beta-hydroxylase inhibitor, SK&F 102698, were assessed in chronically instrumented 1-kidney, 1-clip Goldblatt hypertensive dogs. Blood pressure measured directly from either a carotid loop or from a vascular access port and cardiac output measured by impedence cardiography were monitored following acute (30 and 100 mg/kg, p.o.) and chronic (30 mg/kg/day for 4 days) administration of SK&F 102698. The data indicate that SK&F 102698 failed to alter blood pressure, cardiac output or total peripheral resistance after either acute or chronic administration. It is concluded that dopamine beta-hydroxylase inhibition with SK&F 102698 is not an effective antihypertensive agent in the 1-kidney, 1-clip Goldblatt hypertensive dog model.     

In vivo pharmacological studies with SK&F 94836, a potent inotrope/vasodilator with a sustained duration of action.

1. SK&F 94836 (racemate) was studied in vivo for its cardiovascular properties in cats and dogs. 2. In anaesthetized cats and dogs SK&F 94836 administered intravenously caused increases in left ventricular contractility and decreases in peripheral vascular resistance at similar doses, thus demonstrating the compound to be a mixed acting positive inotropic/vasodilator agent. 3. In conscious instrumented dogs SK&F 94836 was active via the oral as well as intravenous route. 4. The inodilator activity of SK&F 94836 in conscious and anaesthetized animals occurred in association with minimal changes in either blood pressure or heart rate. 5. Detailed studies carried out on anaesthetized cats indicated that SK&F 94836 caused a balanced dilatation of both resistance and capacitance blood vessels. 6. Haemodynamic studies in anaesthetized cats indicated that as a consequence of the inotropic/vasodilator actions, SK&F 94836 caused significant increases in cardiac output and stroke volume. 7. Detailed studies in anaesthetized dogs indicated that significant inodilator activity occurred in the absence of an increase in myocardial oxygen consumption. 8. The duration of action of SK&F 94836 was sustained following both i.v. and oral administration. 9. We conclude that SK&F 94836, as an orally active inotropic/vasodilator agent with a sustained duration in vivo, has potential utility in the treatment of congestive heart failure.     

Correlation of the intrinsic clearance of donepezil (Aricept®) between in vivo and in vitro studies in rat,dog and human

1. Donepezil hydrochloride (Aricept®) is used for the treatment of Alzheimer's disease. Here the correlation of the intrinsic clearance (Cl_int) of donepezil between the in vivo and in vitro states was studied in rat, dog and human. 2. In an experiment with ¹⁴C-donepezil and human microsomes the routes of metabolism were identified as N-dealkylation and O-demethylation, and no unknown metabolites were detected. 3. The Cl_int of donepezil in the male rat, female rat, dog and human liver microsomes were 33.7, 13.4, 37.0 and 6.35 μl/min/mg microsomal protein respectively, and sex difference in rat and interspecies difference in the estimated Cl_int were found. 4. After a single intravenous administration to the male rat, female rat and dog, total plasma clearance (Cl^P_total) was 78.6, 29.5 and 88.3 ml/min/kg respectively, and a sex difference was observed in rat. 5. After a single oral administration to the male rat, dog and healthy volunteer, Cl^P_total/F was 140, 105 and 2.35 ml/min/kg respectively, and remarkable differences were observed between animals and man. 6. The contribution of renal clearance to blood clearance (Cl_r) was low in all species. The predicted in vitro hepatic clearance (Cl_h-pre) was in the rank order: male rat (15.91 ml/min/kg) &gt; dog (7.96) &gt; female rat (7.67) &gt; human (1.04). Although Cl_h-pre was underestimated, Cl_h-pre was significantly correlated with that of ClBtotal in the different animal species and in man, indicating that the in vitro-in vivo ranking order was conserved.     

Evaluation of Using Dog as an Animal Model to Study the Fraction of Oral Dose Absorbed of 43 Drugs in Humans

Purpose. To conduct a retrospective evaluation of using dog as ananimal model to study the fraction of oral dose absorbed (F) of 43drugs in humans and to briefly discuss potential factors that mighthave contributed to the observed differences in absorption. Methods. Mean human and dog absorption data obtained under fastedstate of 43 drugs with markedly different physicochemical andpharmacological properties and with mean F values ranging from 0.015 to1.0 were obtained from the literature. Correlation of F values betweenhumans and dogs was studied. Based on the same references, additionalF data for humans and rats were also obtained for 18 drugs. Results. Among the 43 drugs studied, 22 drugs were virtuallycompletely absorbed in both dogs and humans. However, the overallcorrelation was relatively poor (r² = 0.5123) as compared to the earlier ratvs. human study on 64 drugs (r² = 0.975). Several drugs showed muchbetter absorption in dogs than in humans. Marked differences in thenonliner absorption profiles between the two species were found forsome drugs. Also, some drugs had much longer T_max values andprolonged absorption in humans than in dogs that might be theoreticallypredicted. Data on 18 drugs further support great similarity in F betweenhumans and rats reported earlier from our laboratory. Conclusions. Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery anddevelopment, the present study suggests that one may need to exercise cautionin the interpretation of data obtained. Exact reasons for the observedinterspecies differences in oral absorption remain to be explored.     

Risedronate Pharmacokinetics and Intra- and Inter-Subject Variability Upon Single-Dose Intravenous and Oral Administration

Purpose. To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. Methods. This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. Results. Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. Conclusion. The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or cleared, into bone. The absolute bioavailability of orally administered risedronate is 0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.     

THE ABSORPTION,PHARMACODYNAMICS, METABOLISM AND EXCRETION OF 14C-SUMATRIPTAN FOLLOWING INTRANASAL ADMINISTRATION TO THE BEAGLE DOG

The pharmacodynamics, pharmacokinetics, metabolism, and excretion of ¹⁴C-sumatriptan have been studied in the beagle dog following administration by the intranasal and other routes. The pharmacological response which was monitored, an increase in carotid arterial vascular resistance, correlated with the plasma levels of unchanged sumatriptan following intranasal, intravenous, or intraduodenal administration to the anaesthetised dog. The pharmacokinetics and metabolism of sumatriptan were then confirmed in conscious male and female dogs. Intranasal administration of ¹⁴C-sumatriptan resulted in rapid absorption of part of the dose. The overall bioavailability of sumatriptan was 40–50%. Sumatriptan was eliminated from plasma with a half-life of 1·5 or 1·9 h after intravenous or intranasal dosage respectively. Radioactivity was largely excreted in urine (up to 75% of the dose) with small amounts in the bile and faeces after intravenous and intranasal dosing, as sumatriptan and a major metabolite. The results from these studies suggest that intranasal administration provides a viable method for delivering sumatriptan to the systemic circulation. © 1997 John Wiley & Sons, Ltd.     

Pharmacological studies with SK&F 94120, a novel positive inotropic agent with vasodilator activity

The pharmacological properties of SK&F 94120 on the cardiovascular system have been studied in laboratory animal species. The compound was shown to have positive inotropic activity on hearts from guinea-pig, cat, dog and marmoset in-vitro and in cat and dog in-vivo. These responses in-vivo occurred in association with minimal changes in heart rate. Positive inotropic activity was not caused by SK&F 94120 in rat or hamster hearts in-vitro, thereby indicating a species dependence in myocardial response. SK&F 94120 was shown to have vasodilator activity in cats in-vivo. Detailed studies carried out on anaesthetized cats indicated that the compound caused a balanced dilatation of both resistance and capacitance blood vessels. Haemodynamic studies in anaesthetized cats indicated that, as a consequence of the positive inotropic and vasodilator actions, SK&F 94120 causes significant increases in cardiac output and stroke volume. Studies in conscious dogs showed the compound to be active as a positive inotrope after oral administration. The above properties suggest that this compound possesses useful haemodynamic properties for the treatment of congestive heart failure.     

Reduced Systemic Availability of an Antiarrhythmic Drug,Bidisomide, with Meal Co-administration: Relationship with Region-Dependent Intestinal Absorption

Purpose. The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide. Methods. Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model. Results. Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (–13%) was substantially smaller than the reduction (from –43% to –63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 ± 5.7% and 23.7 ± 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased C_max but not AUC, while viscous homogenized solid meals decreased both C_max and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC. Conclusions. The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.     

Respiratory and Cardiovascular Changes Associated with Toxic Doses of a Peptide Antagonist of Vasopressin in the Rat

SK&F 101926 is a synthetic octapeptide which was designedto promote free water excretion by antagonizing the action ofanti-diuretic hormone. The clinical and pathologic changes inrats resulting from lethal doses of SK&F 101926 have suggestedthat death is associated with respiratory failure and/or cardiovascularcollapse. To define the relationships between respiratory failure,cardiovascular collapse, and death, respiratory and cardiovascularparameters were monitored in anesthetized rats following theintravenous administration of SK&F 101926 at a dosage (3mg/kg) which resulted in 70% mortality. Within 5 min after receivingthis dosage, mean arterial blood pressure was reduced to valuesbetween 30 and 40 mm Hg in all rats. This degree of hypotensionwas well tolerated by some rats and, consequently, was not consideredto be the cause of death. Deaths occurred between 9 and 58 minafter dosing and were preceded by respiratory depression involvingmarked reductions in respiratory rate and the lack of compensatoryincreases in tidal volume. At the time of respiratory arrest,heart rates remained above 200 beats/min, mean arterial bloodpressure remained between 30 and 40 mm Hg, and there were noconsistent changes in dynamic lung compliance or total pulmonaryresistance. Pretreatment of rats with a mast cell stabilizingagent (disodium cromoglycate), a mast cell degranulatung agent(compound 48/80), or a histamine/5-hydroxytryptamine blockingagent (cyproheptadine) prevented the reductions in respiratoryrate and death caused by SK&F 101926. These pretreatmentsalso reduced the effect of SK&F 101926 on blood pressure,but were not able to completely prevent the hypotension. Inconclusion, administration of SK&F 101926 can produce markedchanges in respiratory and cardio vascular functions, with deathappearing to be more closely asso dated with respiratory failurethan with cardiovascular collapse. Furthermore, respiratoryfailure was not related to changes in the mechanical propertiesof the lung, and both the respiratory and cardiovascular changeswhich occurred following the administration of SK&F 101926appear to be dependent on the release of mast cell mediators.