Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats.

The pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats was investigated following intravenous administration of the drug. Mean residence time and steady state volume of distribution were 23-36 min and 0.20-0.311 kg-1, respectively, and were dose independent at the dose of 0.3-3 mumole kg-1. Total body clearance of 8.2 ml min-1 kg-1 over 0.3 mumole kg-1 was slightly increased to 11.3 ml min-1 kg-1 at 3 mumole kg-1. Renal clearance was also increased with the increase of the dose, while hepatobiliary clearance was substantially constant. Ambenonium was highly concentrated in the liver, kidney, spleen, and lung. About 30 per cent of the dose is concentrically stored in the liver at 6 h after administration, and had not disappeared after 24 h.     

Pharmacokinetics and tissue distribution of rifametane, a new 3-azinomethyl-rifamycin derivative, in several animal species

Single and repeated dose experiments in mice, rats, dogs and monkeys are reported in this study to assess the pharmacokinetics and tissue distribution of rifametane, a new semi-synthetic rifamycin with the chemical formula 3-[(1-diethylaminoethylidene)azinomethyl]rifamycin SV (CAS 94168-98-6, SPA-S-565). All the kinetic tests were carried out in comparison with known rifamycin derivatives, as rifampicin (CAS 13292-46-1) or rifamycin SV (CAS 6998-60-3). Mice received single i.v. and oral administration of 10 mg/kg of rifametane or of rifampicin and serum samples were obtained up to 96 h after dosing. The two antibiotics showed similar peak of serum concentrations, but rifametane showed a longer half-life and higher AUC values. In an additional experiment, the tissue/serum ratio after the 10 mg/kg oral dose was lower than unity for lungs and kidneys, while the liver/serum ratio exceeded the unity at all sampling times. After 4 weeks of once weekly administration measurable serum and tissue concentrations were observed, and after twice weekly administration for the same time period some blood and tissue accumulation was seen. Rats were treated with a single intravenous injection of 20 mg/kg of rifametane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), in two separate trials. The serum half-life of the test antibiotic after i.v. dose was 6 times longer than that of rifampicin and the serum concentrations of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of rifametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced very high serum and liver concentrations. Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg of rifampicin. The serum half-life of rifametane resulted 3 times longer than that of rifampicin. Remarkable serum and tissue concentrations were observed after 3-4 weeks of daily oral administration of rifametane at 3, 10, 30 mg/kg dose. Monkeys were given single oral or i.m. administration of 30 mg/kg of rifametane or reference standards (oral rifampicin and i.m. rifamycin SV). The serum concentrations after rifametane were higher and more sustained than those of reference compounds and the half-lives of the test antibiotic were about 2.5 (p.o.) to 6 times (i.m.) longer. The urine excretion of rifametane after a single intravenous dose in rats and a single oral dose in dogs was very low, while rifampicin had a little higher urine concentrations.     

Pharmacokinetics and metabolism of temazepam in man and several animal species.

1 Absorption, excretion and detoxification of temazepam were investigated in man, mouse, rat and dog. Considerable interspecies variation was apparent with respect to excretion and metabolite patterns in blood and urine. Animal species were exposed to equal or greater concentrations of all the metabolites occurring in man. 2 Pharmacokinetics of temazepam in man were investigated in a single dose study at two dose levels, and in a multiple dose study. The results of both studies were analyzed and interpreted with the help of compartmental models. Values were obtained for excretion pattern (0-infinity), half lives (1.95, 0.5, 10.0 and 1.9 h), amounts in all compartments, and for steady-state conditions. 3 The bioavailability of the hard gelatin capsule dosage form was compared with that of a suspension serving as the ideal dosage form, and found to be acceptable.     

Metabolism of meperidine in several animal species

Four new meperidine metabolites were identified by GC-MS in the urine of rats, guinea pigs, rabbits, cats, and dogs. In addition to known meperidine metabolites, 4-ethoxycarbonyl-4-phenyl-1,2,3,4-tetrapyridine (dehydronormeperidine; IV, the N-hydroxydehydro derivative of normeperidine (X), the dihydroxy derivative of meperidine (XII), and the dihydroxy derivative of normeperidine (XIII) were identified. The possible role of the N-hydroxy derivative of normeperidine (IX) in the pharmacological interaction of meperidine (I) with MAO inhibitors, seen selectively in the rabbit (and humans), is discussed. Following the administration of the p-hydroxy derivative of meperidine (VII), the major metabolite was conjugated VII. Trace amounts of the p-hydroxy derivative of normeperidine (VIII), the methoxy hydroxy derivative of meperidine (XI), XII, and XIII also were detected as metabolites of VII. The degree of N-demethylation of VII, both in vitro and in vivo, was small.     

Toxicological evaluation of palytoxin in several animal species

Playtoxin, the toxin extracted from the soft coral Palythoa vestitus, Verril 1928, found in the Hawaiian and other Pacific Islands, is a highly lethal substance in several animal species, and is effective by various routes of administration. Its intravenous LD₅₀ in the dog, rabbit, monkey, guinea pig, rat, and mouse range between 0·033 and 0·45 μg/kg. However, when palytoxin is given by the intragastric or intrarectal route, it is relatively non-toxic. Additionally, playtoxin produces marked irritant and tissue damage when topically applied to skin or eyes, as well as having a general necrotizing action on cells when injected.     

A neuropsychopharmacological study of phenmetrazine in several animal species

The ability of phenmetrazine to elicit gross behavioral and electrographic alterations was examined in view of previous findings. Phenmetrazine elicits stereotyped behavior in rats, cats and dogs. In cats it produces a desynchronized electroencephalogram and elevates reticular formation multiple unit activity. The stereotypy-inducing action of phenmetrazine in cats can be antagonized by α-methyl-p-tyrosine and reserpine. Phenmetrazine appears to have pharmacological properties similar to those of (+)-amphetamine and cocaine.     

Biotransformation of sultopride in man and several animal species

The biotransformation of sultopride has been investigated in rat, rabbit, dog and man. In man sultopride was metabolically stable, and about 90% of an oral dose was excreted in urine unchanged and 4% as oxo-sultopride. Rat, rabbit and dog metabolized sultopride more extensively and excreted less than 40% of an oral dose of 14C-sultopride in urine. Four similar metabolites were excreted by the three animal species but the relative portions differed. The major radioactive component in rat urine was O-desmethyl sultopride, whereas oxo-sultopride and O-desmethyl sultopride were the major urinary metabolites in rabbit. Dog formed N-desethyl sultopride and oxo-sultopride as major urinary metabolites. The male rat excreted smaller amounts of unchanged sultopride in urine than did the female rat. The unchanged sultopride excreted in rat urine was increased slightly by repeated administration.     

Biotransformation of sultopride in man and several animal species

1. The biotransformation of sultopride has been investigated in rat, rabbit, dog and man.

2. In man sultopride was metabolically stable, and about 90% of an oral dose was excreted in urine unchanged and 4% as oxo-sultopride.

3. Rat, rabbit and dog metabolized sultopride more extensively and excreted less than 40% of an oral dose of ¹⁴C-sultopride in urine.

4. Four similar metabolites were excreted by the three animal species but the relative portions differed. The major radioactive component in rat urine was O-desmethyl sultopride, whereas oxo-sultopride and O-desmethyl sultopride were the major urinary metabolites in rabbit. Dog formed N-desethyl sultopride and oxo-sultopride as major urinary metabolites.

5. The male rat excreted smaller amounts of unchanged sultopride in urine than did the female rat.

6. The unchanged sultopride excreted in rat urine was increased slightly by repeated administration.     

Pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ARA-C) deamination in several species

The pharmacokinetics of 1-β-d-arabinofuranosylcytosine (Ara-C) and 1-β-d-arabinofuranosyluracil (Ara-U) are related to enzyme kinetics in vitro in mice, monkeys, dogs and humans by means of a mathematical model. The model is physiologic and permits the incorporation of chemical reactions in appropriate anatomic sites with kinetic characteristics of their local environment. A lean tissue compartment plays an important role as a reservoir. The kidney clearance of Ara-C exhibits essentially the same variation with body weight as inulin.     

Effect of AA-861, a selective 5-lipoxygenase inhibitor, on models of allergy in several species

The effects of 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA-861), a selective 5-lipoxygenase inhibitor, on immunological or non-immunological release of slow reacting substance of anaphylaxis (SRS-A) and histamine and its effects on experimental asthma were investigated. AA-861 showed a dose-dependent inhibition of SRS-A release, with no effect on histamine release from passively sensitized guinea pig, monkey (M. irus) and human lung fragments. An analysis of the anaphylactic diffusate from the human lung fragments, using the combined technique of high performance liquid chromatography and radioimmunoassay, revealed that AA-861 markedly suppresses biosynthesis of the leukotrienes. However, this drug inhibits the release of histamine as well as SRS-A from lung fragments of anaphylactic monkey (M. mulatta) and in the Ca ionophore-stimulated rat peritoneal cavity. AA-861 suppressed the anaphylactically-induced airway resistance in mepyramine- and cimetidine-treated guinea pigs. These results suggest that AA-861 may be clinically effective for treating allergy-related asthma by modulating the 5-lipoxygenase pathway and that an inhibitory mechanism of histamine release by AA-861 may be present in some species.     

Repeat oral dosing of prasugrel, a novel P2Y12 receptor inhibitor, results in cumulative and potent antiplatelet and antithrombotic activity in several animal species

Antiplatelet and antithrombotic activity of multiple oral dosing of prasugrel were evaluated in several animal species. Prasugrel's active metabolite concentration-relatedly inhibited in vitro ADP-induced aggregation of rat, rabbit, dog, monkey and human platelets. Oral administration of prasugrel to dogs (0.03-0.3 mg/kg/day) and monkeys (0.1 and 0.3 mg/kg/day) once a day for 14 days resulted in potent, dose-related and cumulative inhibition of ADP-induced platelet aggregation. The inhibitory effects reached a plateau on days 3 to 5 and thereafter were maintained during dosing. Inhibition decreased gradually after cessation of dosing with near full recovery by 7 days after last dose. Antiplatelet and antithrombotic activity of prasugrel and clopidogrel were further examined in rats. Multiple oral dosing of prasugrel (0.3-3 mg/kg/day) to rats resulted in more potent inhibition of platelet aggregation compared to clopidogrel (3-30 mg/kg/day) and ticlopidine (30-300 mg/kg/day). Separate experiments confirmed that platelet inhibition was associated with inhibition of [(3)H]-2-methylthio-ADP binding to rat platelets. In a rat model of electrically-induced arterial thrombosis, prasugrel (0.1-1 mg/kg/day, p.o.) significantly prolonged the time to arterial occlusion and increased the duration of arterial patency. The inhibition of platelet aggregation of prasugrel was about 10 and 300 times more potent than clopidogrel and ticlopidine, respectively. Overall these results show that in several species multiple oral administration of prasugrel results in more potent inhibition of platelet aggregation and thrombus formation than clopidogrel and ticlopidine, and that these effects are mediated by inhibition of platelet ADP receptors.     

Pharmacokinetics of sulfisoxazole compared in humans and two monogastric animal species

The pharmacokinetic profile of sulfisoxazole was studied and compared in dogs, swine, and humans. The trial was conducted over a 72-hr period after intravenous administration and a 96-hr period after oral administration in dogs and swine. In humans, the trial was conducted over an 8-hr period after oral administration. A two-compartment model system was used to define the pharmacokinetic profile. The mean half-lives for the distribution phase were 4.08, 1.30, and 0.56 hr in dogs, swine, and humans, respectively. For the elimination phase, the mean half-lives were 33.74, 46.39, and 7.40 hr in dogs, swine, and humans, respectively. The mean volume of the central compartment was approximately the same in dogs and swine, 10.6 and 10.5 liters, respectively. Humans had a smaller volume of distribution, 7.7 liters. The steady-state volumes of distribution were 17.2, 30.3, and 16.2 liters in dogs, swine, and humans, respectively. Dogs and swine excreted 42.2 and 30.7%, respectively, of the intravenous dose and 29.4 and 18.3%, respectively, of the oral dose. The bioavailability was 69.8% in dogs and 100.0% in swine. The fraction of drug bound ranged from 30 to 50% in dogs, 40 to 60% in swine, and 25 to 40% in humans.     

Pharmacological aspects of the acetylcholinesterase inhibitor galantamine

Several lines of evidence suggest that cholinergic deficits may contribute to the pathophysiology of psychiatric disorders as well as Alzheimer's disease. There is growing clinical evidence that galantamine, currently used for the treatment of Alzheimer's disease, may improve cognitive dysfunction and psychiatric illness in schizophrenia, major depression, bipolar disorder, and alcohol abuse. Since galantamine is a rather weak acetylcholinesterase inhibitor, but has additional allosteric potentiating effects at nicotinic receptors, it affects not only cholinergic transmission but also other neurotransmitter systems such as monoamines, glutamate, and γ-aminobutyric acid (GABA) through its allosteric mechanism. It is likely that these effects may result in more beneficial effects. To understand the underlying mechanism for the clinical effectiveness of galantamine, neuropharmacological studies have been performed in animal models of several psychiatric disorders. These studies suggest that not only the nicotinic receptor-modulating properties but also the muscarinic receptor activation contribute to the antipsychotic effect and improvement of cognitive dysfunction by galantamine. This review summaries the current status on the pharmacology of galantamine, focusing on its effect on neurotransmitter release and pharmacological studies in animal models of psychiatric disorders.     

Pharmacokinetics of NS-49, a phenethylamine class alpha(1A)-adrenoceptor agonist, at therapeutic doses in several animal species and interspecies scaling of its pharmacokinetic parameters.

The pharmacokinetics of NS-49, a newly developed phenethylamine class alpha(1A)-adrenoceptor agonist, was investigated in rats, rabbits, and dogs given intravenous and oral doses that have little effect on the renal blood flow rate (approximating the range of clinical doses). A three-compartment open model adequately described the plasma NS-49 profiles with respective elimination half-lives of 18, 19, and 13 h after intravenous administration of NS-49 to rats, rabbits and dogs. After oral administration, the NS-49 plasma concentrations reached their maximums within 1.5 h in all the species tested, then decreased as in intravenous administration. The systemic availability was 80% for the rats, 70% for the rabbits, and 101% for the dogs. From the pharmacokinetic parameter values for these three species, we predicted human pharmacokinetics of NS-49 after oral administration with an animal scale-up approach. The area under the plasma concentration-time curve (AUC) after oral administration, as well as the total body clearance showed an excellent allometric relationship to body weight across the three species. The oral AUC value for humans therefore could be predicted from this correlation. The predicted value agreed well with the observed value in the clinical phase I study. It was difficult to predict the plasma concentration profile of NS-49 for humans after oral administration because the absorption rate constant (k(a)) that is essential for estimation of the maximum concentration exhibited no correlation across the species tested. But we approximately could simulate the plasma concentration profile of NS-49 for humans by using the k(a) value for the rats or rabbits.     

Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.     

Stereotyped activities produced by amphetamine in several animal species and man

Summary Experiments with chickens, pidgeons, mice, rats, guinea-pigs, cats, dogs, squirrel-monkeys and chimpanzees show that stereotyped activity can be produced by amphetamine in doses of 1–20 mg/kg in all these species ranging from birds to primates.In man amphetamine in similar dose, i.e. higher than the therapeutic doses, can produce a psychosis, which so closely resembles schizophrenia, that misdiagnoses have been made. All the known symptoms of schizophrenia are reported, including stereotyped activity.This investigation was supported by grants from Knud Højgaards Fond and from the Copenhagen Hospital Administration. The authors want to thank Mrs. Reiko Okada and Mrs. Johanne Mengel for translation of Japanese and Italian literature.     

Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats

This study is the first report of the pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats after i.v. and oral administration. Apicidin was injected intravenously at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg. The terminal elimination half-life (t1/2), systemic clearance (Cl) and steady-state volume of distribution (Vss) remained unaltered as a function of dose, with values in the range 0.8-1.1 h, 59.6-68.0 ml/min/kg and 2.4-2.7 l/kg, respectively. Whereas, the initial serum concentration (C0) and AUC increased linearly as the dose was increased. Taken together, the pharmacokinetics of apicidin were linear over the i.v. dose range studied. The extent of urinary and biliary excretion of apicidin was minimal (0.017%-0.020% and 0.049% +/- 0.016%, respectively). Oral pharmacokinetic studies were conducted in fasting and non-fasting groups of rats at a dose of 10 mg/kg. The Tmax, Cl/F and Vz/F were in the range 0.9-1.1 h, 520.3-621.2 ml/min/kg and 67.6-84.4 l/kg, respectively. No significant difference was observed in the oral absorption profiles between the two groups of rats. Apicidin was poorly absorbed, with the absolute oral bioavailability of 19.3% and 14.2% in fasting and non-fasting rats.     

Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man

OBJECTIVE: This study investigated the pharmacokinetics of the catechol-O-methyltransferase (COMT) inhibitor entacapone by giving simultaneously stable non-radioactive isotope 13C-entacapone intravenously (i.v.) and unlabelled entacapone orally. In comparison with a crossover design, the simultaneous i.v. and oral administration made it possible to minimise intra-individual variation, sample size and the duration of the study and still obtain accurate pharmacokinetic data. METHODS: Eight healthy male volunteers were enrolled in this study. They were given a 20-mg i.v. dose of 13C-entacapone as a 1-mg/ml infusion at a constant rate of 5 mg/min over 4 min and a 100-mg dose of unlabelled entacapone orally immediately after the infusion. Blood samples were drawn at -5 (before onset of infusion), 0 (upon termination of infusion), 2, 5, 10, 20, 30 and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after the tablet ingestion. Urine during the 48 h after dosing was collected in fractions. Concentrations of 13C-entacapone and entacapone in plasma samples and urine fractions were determined using gas chromatography-mass spectrometry. RESULTS: The decay of i.v. 13C-entacapone in plasma was tri-exponential and its pharmacokinetics were described using an open three-compartment model. The volume of the central compartment (Vc) and the volume of distribution at steady state (Vss) were 0.08+/-0.03 l/kg and 0.27+/-0.10 l/kg, respectively. Total plasma clearance (Cltot) averaged 11.7+/-1.9 ml/min kg(-1). The half-lives for the distribution phase and for the rapid and terminal elimination phases (t1/2alpha, t1/2beta and t1/2gamma) were 0.05+/-0.01 h, 0.38+/-0.16 h and 2.40+/-1.70 h, respectively. The terminal elimination phase accounted for only 9% of the total area under the plasma concentration-time curve (AUC), which was 409 +/- 98 ng h/ml after the i.v. dose. Oral entacapone was absorbed rapidly with a time to reach the peak concentration (tmax) of 0.9+/-0.4 h, a maximum concentration (Cmax) of 457+/-334 ng/ml and an AUC of 497+/-118 ng h/ml. During the 48 h after dosing, the recovery of free and conjugated unchanged 13C-entacapone in urine was 38.1+/-7.2% of the i.v. dose and the recovery of free and conjugated unchanged entacapone 13.3+/-3.9% of the oral dose. The bioavailability of oral entacapone was 25% based on the AUC values and 35% based on urinary excretion. CONCLUSION: The results of the present study using stable isotope technique indicate that entacapone is rapidly absorbed, distributed to a small volume and rapidly eliminated by mainly non-renal routes. The pharmacokinetic profile of entacapone provides the rationale for a concomitant and frequently repeated simultaneous dosing of entacapone with levodopa and dopa decarboxylase inhibitors in the treatment of Parkinson's disease. This study confirmed the previously published data and fully support the validity of the technique used.