Oral activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in rats, dogs and monkeys

The purpose of this study was to evaluate the growth hormone (GH) releasing activity of orally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in rats, dogs and monkeys. Rats were administered GHRP-6 orally by gavage or parenterally through femoral artery catheters. Blood was collected before and after GHRP-6 administration for estimation of plasma GH and comparison of GH changes resulting from enteral and parenteral administration of the peptide. GHRP-6 was administered to dogs intravenously (i.v.) through cephalic vein catheters, intragastrically (i.g.) through esophagostomy tubes or intraduodenally (i.d.) through vascular access ports, and blood was collected before and after peptide administration for estimation of plasma GH. Cynomolgus monkeys were administered GHRP-6 i.g., and blood was collected from abdominal aorta for estimation of changes in plasma GH. Enteral activity of GHRP-6 was observed in all 3 species tested. In rats, ED50's for enteral and parenteral administration of GHRP-6 were 4 mg/kg and 28 micrograms/kg, respectively. Thus in rats, enterally administered GHRP-6 was 0.7% as bioactive as the parenterally administered peptide. In dogs GHRP-6 was slightly less potent than in rats, with ED50's for i.g. and i.v. administration approximately 15 mg/kg and 125 micrograms/kg, respectively. However, enteral potency of GHRP-6 in dogs was 0.8% of parenteral potency, and thus, comparable to that in rats. Additionally, comparison of plasma GH levels following i.g. vs i.d. administration in dogs suggested greater activity by the i.d. route. Monkeys were the species most sensitive to enterally administered GHRP-6, with plasma GH increased in those receiving i.g. doses as low as 0.3 mg/kg and an ED50 of 0.75 mg/kg compared to 4 and 15 mg/kg in rats and dogs, respectively. The results of this study demonstrate that GHRP-6 releases GH when administered directly into the gastrointestinal tract. Although enteral activity is approximately 1% of parenteral activity, GHRP-6 is potent, especially in primates which require relatively low doses to provoke GH release. These data suggest that orally active GHRP-6 may provide a practical therapeutic alternative to parenterally administered peptides such as GHRH, especially if enteral activity is enhanced with appropriate formulation.     

Growth hormone, thyrotropin and prolactin responses to simultaneous administration of human growth hormone-releasing factor and thyrotropin releasing hormone in the bovine

The effects of intravenous injection of synthetic human pancreatic growth hormone-releasing factor-44-NH2 (hpGRF-44) and synthetic thyrotropin releasing hormone (TRH), or hpGRF-44 in combination with TRH on growth hormone (GH), thyrotropin (TSH), and prolactin (PRL) release in dairy female calves (6- and 12-month-old) were studied. When 0.25 microgram of hpGRF-44 per kg of body weight (bw) was injected in combination with TRH (1.0 microgram per kg of bw), the mean plasma GH concentration of the 12-month-old calves rose to a maximum level of 191.5 ng/ml (P less than 0.001) at 15 min from the value of 6.8 ng/ml before injection at 0 min. The maximum level was 3.1 and 6.1 times as high as the peak values obtained after injection of hpGRF-44 (0.25 microgram per kg of bw) and TRH (1.0 microgram per kg of bw), respectively (P less than 0.001). The area under the GH response curve for the 12-month-old calves for 3 hr after injection of hpGRF-44 in combination with TRH was 2.5 times as large as the sum of the areas obtained by hpGRF-44 and TRH injections. In contrast, the mean plasma GH level was unchanged in saline injected calves. The magnitudes of the first and the second plasma GH responses in the 6-month-old calves to two consecutive injections of hpGRF-44 in combination with TRH at a 3-hr interval were very similar. The peak values of plasma GH in the calves after hpGRF-44 injection were 2-4 times as high as those after TRH injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding Study of Platinum Originating from Dicycloplatin, a Novel Antitumor Supramolecule, in Rats and Dogs by ICP-MS

Dicycloplatin, as a new antitumor supramolecule, was considered to have higher solubility and higher stability compared with carboplatin. The aim of the present study was to evaluate the pharmacokinetic characteristics of platinum originating from dicycloplatin. A rapid, sensitive, and specific method with inductively coupled plasma mass spectrometry (ICP-MS) has been developed for the determination of platinum in bio-samples. The study was performed in male rats and dogs at a single dose of 10 and 5 mg kg(-1) separately by intravenous injection. Pharmacokinetic parameters were calculated by non-compartmental method, and the dose of platinum was used in the calculation of these parameters. Results showed that plasma concentrations of platinum began to decrease rapidly initially but decline slowly with a long terminal phase. The mean half-life was 27.39 and 100.98 and clearance was 0.77 and 0.08 L/h/kg for rats and dogs separately. Tissue distribution showed that platinum originating from dicycloplatin had a certain distribution in testis and prostate. Plasma protein binding proportion of platinum was increased with time. In conclusion, this research investigated the pharmacokinetic characteristics including plasma kinetics, tissue distribution, and plasma protein binding of platinum originating from dicycloplatin in rats and dogs in detail for the first time by ICP-MS.     

Studies on the metabolism of testosterone trans-4-n-butylcyclohexanoic acid in the cynomolgus monkey, Macaca fascicularis

Metabolism of intravenously administered testosterone trans-4-n-butylcyclohexanoate (T bucyclate), a potent, long-acting androgen, was studied in cynomolgus monkeys (Macaca fascicularis). About 5% of the radioactivity of a dose of doubly labeled ester (¹⁴C, ³H) was excreted via the gastrointestinal tract. Most of the administered radioactivity was excreted in the urine within 120 h. No intact T bucyclate was recovered from either compartment. Tritium attributed to bucyclic acid and its metabolites was excreted rapidly (peak excretion was at 6 h after injection), while ¹⁴C excretion, attributed to testosterone and its metabolites, extended over 4 days. Testosterone metabolites were excreted predominantly as sulfate esters. Analysis of urinary products derived from the bucyclic acid moiety of T bucyclate showed no products susceptible to glucuronidase treatment, and showed a mixture of unidentified solvolyzable and unconjugated products. No unmetabolized trans-4-n-butylcyclohexanoic acid was detected in urine or feces. It is concluded that metabolism of testosterone bucyclate is initiated in vivo in cynomolgus monkeys by hydrolysis of ester to testosterone and bucyclic acid. The bucyclate side chain is rapidly cleared, and the testosterone is retained in the circulation.     

Toxicity and genotoxicity in Astyanax bimaculatus (Characidae) induced by microcystins from a bloom of Microcystis spp

Studies of genotoxicity in fish caused by cyanobacterial microcystins can be useful both in determining the sensitivity of native species, as well as comparing exposure routes. The genotoxicity caused by the microcystins LR and LA from a bloom collected in a eutrophic lake, was revealed in the fish Astyanaxbimaculatus, a native species from South America. LC50 (72 h) was determined as 242.81 μg L (-1) and LD50 (72 h) as 49.19 μg kg (-1) bw. There was a significant increase of DNA damage in peripheral erythrocytes, following intraperitoneal injection (ip) with tested concentrations of 24.58 μg kg (-1) bw and 36.88 μg kg (-1) bw, as well as through body exposure to a concentration of 103.72 μg L (-1) . Micronucleus (MN) induction was observed after ip injections of 24.58 μg kg (-1) bw and 36.88 μg kg (-1) bw for 72 h, as well as following body exposure for 72 at 103.72 μg L (-1) . Thus, both exposure routes resulted in MN induction and DNA damage. Apoptosis-necrosis testing was carried out only by ip injection with concentrations of 24.58 μg kg (-1) bw and 36.88 μg kg- 1 bw. Exposure to microcystins at lower concentrations induced more apoptosis than necrosis in peripheral erythrocytes, whereas exposure at higher concentrations gave rise to both conditions. Thus, Astyanax bimaculatus can be considered as a species sensitive to the genotoxic effects caused by microcystins.     

Acetaminophen in the guinea pig: metabolite identification in blood, urine, and bile

The biotransformation of single acute oral doses of acetaminophen (100 mg/kg body weight) in adult male guinea pigs was studied by collecting serial blood, urine, and bile samples post-treatment and identifying and quantitating the concentrations of parent drug and excretory products by high performance liquid chromatography. The plasma half-life (beta t/2) (mean +/- SD) of acetaminophen was 1.87 +/- 0.30 h, while that of the only metabolite detected in plasma, the glucuronide, was 2.41 +/- 0.64 h. In 24-h urine samples, the predominant product was the glucuronide (90%) with a small amount of the sulphate conjugate (7.0%) and approximately 3.0% acetaminophen. In bile, the glucuronide was the major metabolite detected initially but, with time, this product decreased concomitantly with an increase in the cysteinyl conjugate. No sulphate was detected in bile but two unidentified metabolites were detected, having distinct column retention times and comprising approximately 6-10% of the total excretory products. The results demonstrated that glucuronidation is a high capacity biotransformation pathway for acetaminophen in this species, only small amounts of other conjugated products being detectable under usual circumstances.     

Species differences in the metabolism of norephedrine in man, rabbit and rat

1. (+/-)-2-Amino-1-phenyl[1-(14)C]propan-1-ol ([(14)C]norephedrine) was administered orally to man, rat and rabbit and the metabolites excreted in the urine were identified and measured. Pronounced species differences in the metabolism of the drug were found. 2. Three male human subjects, receiving 25mg each of [(14)C]norephedrine hydrochloride, excreted over 90% of the (14)C in the first day. The main metabolite was the unchanged drug (86% of the dose) and minor metabolites were hippuric acid and 4-hydroxynorephedrine. 3. In rats given 12mg of the drug/kg almost 80% of the (14)C administered was excreted in the first day. The major metabolites in the urine were the unchanged drug (48% of the dose), 4-hydroxynorephedrine (28%) and trace amounts of side-chain degradation products. 4. Rabbits given 12mg of the drug/kg excreted 85-95% of the dose of (14)C in the urine in the first 24h after dosing. The major metabolites in the urine were conjugates of 1,2-dihydroxy-1-phenylpropane (31% of the dose) and of 1-hydroxy-1-phenylpropan-2-one (27%) and hippuric acid (20%). The unchanged drug was excreted in relatively small amounts (8%).     

The metabolic fate of amphetamine in man and other species

1. The fate of [(14)C]amphetamine in man, rhesus monkey, greyhound, rat, rabbit, mouse and guinea pig has been studied. 2. In three men receiving orally 5mg each (about 0.07mg/kg), about 90% of the (14)C was excreted in the urine in 3-4 days. About 60-65% of the (14)C was excreted in 1 day, 30% as unchanged drug, 21% as total benzoic acid and 3% as 4-hydroxyamphetamine. 3. In two rhesus monkeys (dose 0.66mg/kg), the metabolites excreted in 24h were similar to those in man except that there was little 4-hydroxyamphetamine. 4. In greyhounds receiving 5mg/kg intraperitoneally the metabolites were similar in amount to those in man. 5. Rabbits receiving 10mg/kg orally differed from all other species. They excreted little unchanged amphetamine (4% of dose) and 4-hydroxyamphetamine (6%). They excreted in 24h mainly benzoic acid (total 25%), an acid-labile precursor of 1-phenylpropan-2-one (benzyl methyl ketone) (22%) and conjugated 1-phenylpropan-2-ol (benzylmethylcarbinol) (7%). 6. Rats receiving 10mg/kg orally also differed from other species. The main metabolite (60% of dose) was conjugated 4-hydroxyamphetamine. Minor metabolites were amphetamine (13%), N-acetylamphetamine (2%), norephedrine (0.3%) and 4-hydroxynorephedrine (0.3%). 7. The guinea pig receiving 5mg/kg excreted only benzoic acid and its conjugates (62%) and amphetamine (22%). 8. The mouse receiving 10mg/kg excreted amphetamine (33%), 4-hydroxyamphetamine (14%) and benzoic acid and its conjugates (31%). 9. Experiments on the precursor of 1-phenylpropan-2-one occurring in rabbit urine suggest that it might be the enol sulphate of the ketone. A very small amount of the ketone (1-3%) was also found in human and greyhound urine after acid hydrolysis.     

Stereoselective metabolism of the herbicide fluroxypyr methylheptyl ester in rabbits

We investigated the stereoselective degradation kinetics of fluroxypyr methylheptyl ester (FPMH) in rabbits using a chiral high-performance liquid chromatographic method. In 20% rabbit plasma, the half lives of (+)-FPMH and (-)-FPMH were 2.5 and 10.9 min, respectively. Thus, the enantioselective degradation was faster for (+)-FPMH than for (-)-FPMH in rabbit plasma in vitro, and there was no chiral conversion or transformation during incubation of the plasma. The degradation of (+)-FPMH was also much faster than that of the (-)-FPMH in the kidney, lung, and muscle after the intravenous administration of 50 mg/kg racemic FPMH (rac-FPMH), whereas the concentrations of FPMH were below the limit of quantification in other tissues. Furthermore, 98% rac-FPMH was quickly (within 10 min) hydrolyzed to fluroxypyr (FP) in rabbit liver microsomes. Therefore, we examined FP in rabbit plasma and tissues in vivo. We detected FP in all tissues; its concentration was higher in the urine than in the other tissues. FP was rapidly excreted unchanged, principally in the urine. The data presented here are important for a more thorough understanding of this pesticide and should be useful for its full environmental assessment.     

Pharmacokinetics of 3H-cicaprost in healthy volunteers

Cicaprost (5-[(E)-(1S,5S,6S,7R)-7-hydroxy-6-[(3S,4S)-3-hydroxy-4-methylnona- 1,6- diinyl]-bicyclo[3.3.0]octan-3-yliden]-3-oxapentanoic acid, ZK 96 480) is a novel PGI2-derivative, which is chemically stable and not subject to metabolic degradation in rats and cynomolgus monkeys. The pharmacokinetics of Cicaprost were studied in six healthy volunteers (age: 54-74 y) after i.v. infusion (2.1 micrograms over 60 min) and p.o. dosage (7.6 micrograms) of the tritiated compound. All treatments were well-tolerated by the test subjects. At the end of the infusion plasma levels of approximately 100 pg/ml were reached, declining biphasically with half-lives of 3-4 min and 64 +/- 21 min. Total clearance was 3.8 +/- 0.5 ml/min/kg. The oral dosage resulted in peak plasma levels of 251 +/- 90 pg/ml occurring at 23 +/- 5 min post dose. The terminal half-life in the plasma was 115 +/- 30 min. Gastro-intestinal absorption and absolute bioavailability of Cicaprost was complete. After both routes of administration approx. 60% of dose was excreted with the urine within 24 h, whereas fecal 3H-excretion lasted for several days and accounted for approx. 35%. Radiochromatography revealed that Cicaprost was metabolically stable in plasma and urine. In the feces several degradation products were observed apart from approx. 30% of the dose fraction being excreted unchanged by that route. The present results demonstrate that Cicaprost is an orally completely bioavailable, metabolically stable PGI2-mimetic which may be an ideal candidate for oral therapy because of its pharmacokinetic characteristics.     

Fate of mimosine administered orally to sheep and its effectiveness as a defleecing agent.

Mimosine was administered orally to Merino sheep once daily for periods of 1-3 days, either as the isolated compound or in the foliage of Leucaena leucocephala. A single daily dose of mimosine of 450 or 600 mg/kg body weight was effective for defleecing sheep. A daily dose rate of 300 mg/kg was effective for defleecing sheep if given on two successive days. The effectiveness of a treatment for defleecing sheep was related to the concentration of mimosine in plasma following dosing; defleecing ensued when the concentration of mimosine in plasma was maintained above 0-1 mmol/l for at least 30 h. The main products excreted in urine were mimosine and 3,4-dihydroxypyridine (DHP); small amounts of mimosinamine were also excreted. During the first day following dosing, the major excretory product was mimosine; DHP was an important component during the second and third days. In the three days following the start of dosing, between 32 and 53% of the mimosine given was accounted for as mimosine in the urine. Following an intravenous infusion of mimosine, no DHP was detected in urine; most of the mimosine was excreted intact but a small amount (c. 9%) was excreted as mimosinamine.     

Differential effects of N-methyl-D-aspartate receptor stimulation on growth hormone secretion at specific stages of postnatal development of the male rhesus monkey

The present study attempts to examine the role of N-methyl-D-aspartate (NMDA) receptor in the central regulation of growth hormone (GH) secretion during specific stages of pubertal development of the male rhesus monkey (Macaca mulatta). Infantile (n=4), prepubertal (n=5), peripubertal (n=5) and adult (n=5) intact male rhesus monkeys were given an agonist of NMDA receptor, N-methyl-D,L-aspartate (NMA) (15 mg/kg BW) through a teflon cannula implanted in the saphenous vein. Blood samples were collected 20-60 min before and 40-80 min after the injection of the drug at 10-20 min intervals. NMA was dissolved in normal saline immediately before use and passed through a 0.22 microm filter at the time of injection. All bleedings were carried out under ketamine hydrochloride anesthesia (initial dose 5 mg/kg BW, im followed by 2.5 mg/kg at 30 min intervals). The plasma levels of GH and testosterone (T) were determined by using specific assay systems. The hypothalamic-somatotrope activity under basal conditions was studied by averaging all the GH concentrations obtained before NMA injection, whereas the sensitivity of NMDA receptor to NMA stimulation was determined by comparing basal GH levels immediately before NMA injection at 0 min and GH concentrations obtained 10 min after the injection. The mean basal plasma concentrations of GH in the four groups of animals showed marked age-related differences. The levels of GH were found to be higher in infantile and peripubertal monkeys as compared to those of prepubertal and adult animals. A single iv injection of NMA produced differential effects on GH secretion during specific stages of postnatal development depending upon the level of GH secretion under basal conditions. Whereas NMA had no demonstrable effect on GH secretion in infantile and peripubertal animals in which the basal GH levels were high, it produced pronounced effects on GH secretion in prepubertal and adult monkeys wherein baseline GH concentrations were low. In conclusion, the present study suggests that the glutamatergic component of the control system that governs GH secretion by utilizing NMDA receptor may participate in regulation of age-related changes in the secretion of GH in the male rhesus monkey.     

Pharmacokinetics of florfenicol in cod Gadus morhua and in vitro antibacterial activity against Vibrio anguillarum

The pharmacokinetic profile of the antibacterial agent florfenicol was studied in plasma after intravenous (i.v.) injection and in plasma, muscle and liver following oral (p.o.) administration to cod Gadus morhua, held in seawater at 8 degrees C and weighing 100 to 200 g. Following i.v. injection, the plasma drug concentration-time profile showed 2 distinct phases. The plasma distribution half-life (t1/2alpha) was estimated to be 1.6 h, the elimination half-life (t1/2beta) to be 43 h, the total body clearance (ClT) to be 0.015 1 kg(-1) h(-1) and mean residence time (MRT) to be 74 h. The volume of distribution at steady state, Vd(ss), was calculated to be 1.1 l kg(-1). Following p.o. administration, the bioavailability was estimated to be 91%, the peak plasma concentrations (Cmax) to be 10.8 microg ml(-1) and the time to peak plasma concentrations (Tmax) to be 7 h. Corresponding Cmax and Tmax values were 13.0 microg g(-1) and 9 h, respectively, in muscle and 12.1 microg g(-1) and 9 h, respectively, in liver. The in vitro minimum inhibitory concentration (MIC) values of florfenicol against 3 Vibrio anguillarum strains isolated from diseased cod (A-21, HI-610, HI-618) were 0.5 microg ml(-1) for all 3 strains.     

Pharmacokinetics and biotransformation of the prostacyclin analogue,ZK 36 374, in the beagle dog

Tritium-labelled ZK 36 374 was administered to three female beagle dogs intravenously and orally in a dose of 200 μg/kg. Blood and plasma levels and excretion with urine and feces of drug and metabolites were measured. ZK 36 374 was rapidly absorbed. The bioavailability was estimated as about 10 % of the dose. The concentration of radio-labelled compounds in the plasma declined in three phases with half-lives of 3 min, 46 min and approx. 2 d. The half-life of the unchanged drug was 14 min. ZK 36 374 was totally metabolized and excreted mainly via the kidneys.     

Urinary and fecal immunoglobulin A, cortisol and 11-17 dioxoandrostanes, and serum cortisol in metabolic cage housed female cynomolgus monkeys (Macaca fascicularis)

BACKGROUND AND METHODS: Quantitative enzyme-immunoassays of urinary and fecal immunoglobulin A (IgA), cortisol and 11-17-dioxoandrostanes (11,17-DOA), and serum cortisol in eight metabolic-cage-housed female cynomolgus monkeys were performed. The monkeys were divided into two groups, B and NB. Group B animals were blood sampled every 6 hours, whereas Group NB animals were not handled/blood sampled. RESULTS: No differences were recorded between the amounts of feces and urine excreted by the two groups. Group B animals excreted more urinary cortisol than did Group NB animals indicating that restraint-blood sampling resulted in a stress response. Excreted amounts of IgA and 11,17-DOA (urine and feces) did not differ between the groups. CONCLUSIONS: Urinary cortisol was a reliable marker of the stress associated with repeated blood sampling. Declining amounts of excreted urinary cortisol indicated that cynomolgus monkeys acclimated quickly to repeated blood sampling in metabolism cages. Within and between animal variation in amounts of feces voided demonstrated the importance of expressing fecal markers as 'amounts excreted per time unit per kg body weight' rather than just measuring the concentrations in fecal samples.     

Plasma kinetics and urine profile of ethyl glucosides after oral administration in the rat

In this in vivo study, the time course of plasma concentration and the urinary excretion of ethyl alpha-D-glucoside (alpha-EG) and ethyl beta-D-glucoside (beta-EG) were investigated in rats after a single oral dose of 4 mmol/kg body weight. Maximal plasma concentrations of both alpha-EG and beta-EG (EGs) reached approximately 3 mM at 1 h after oral administration and then decreased rapidly. Approximately 80% of EGs administered were excreted into the urine during the first 6 h. Within 24 h, cumulative urinary alpha-EG and beta-EG excretions were estimated to be 87.2+/-7.9% and 85.4+/-5.0%, respectively. Traces of both EGs were detected in plasma and urine 24 h after oral ingestion. The results of this study indicate that almost all of both EGs was rapidly absorbed into the blood stream and easily excreted into the urine after oral administration, and that a small amount of them remained in the rat body 24 h after administration.     

Adrenocorticotropin secretion rates following histamine injection in adult and newborn dogs.

The metabolic clearance rate (MCR) for ACTH in adult dogs was previously shown not to vary significantly with varying plasma ACTH concentrations or among dogs. This is confirmed here for pups aged 1-7 days. Hence, ACTH secretion rates can be continuously calculated from a continuous function of plasma ACTH vs. time. Each of seven adult dogs under Nembutal anesthesia received two or three intravenous (i.v.) injections of histamine with increasing doses. The first injections in each dog ranged from 7 to 50 mug/kg, while the last dose was 62-108 mug/kg. A total of 16 injections were given. Twelve pups (two litters of six) aged 1-7 days each received one injection of histamine of 76-116 mug/kg (i.v.). ACTH concentrations in plasma were determined by an adrenal cell suspension bioassay before, and 6 times after each injection. Nine pups also underwent determinations of their MCR for ACTH, with plateau concentrations determined at three times during an ACTH infusion. Continuous curves of ACTH secretion rates were calculated for all 28 histamine injections, showing that all except the 1-day-old pups secrete considerable ACTH when stressed. Compared to adult dogs, the pups show lower secretion rate peaks and shorter periods of rapid secretion. Changes in plasma glucocorticoids also suggest that the adrenal cortex of newborn dogs can respond to ACTH by increased glucocorticoid secretion.     

Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys

Norfloxacin, a new orally active antibiotic, was investigated in cynomolgus monkeys for potential developmental toxicity. Fifty-seven monkeys were administered a control vehicle or norfloxacin by nasogastric gavage during the major period of organogenesis on gestational days (GD) 21 through 50 at doses of 0, 50, 100, 150, or 200/300 mg/kg/day. There was no evidence of teratogenicity at any dose level. Maternotoxicity and a significant increase in embryolethality occurred following doses of 200/300 mg/kg/day. The maternotoxicity was not expected based on range-finding studies in nonpregnant female monkeys, which showed no signs of toxicity in doses up to 500 mg/kg/day. Additional studies were conducted to determine if norfloxacin caused similar toxicity later in gestation. Forty-six pregnant monkeys were dosed with a control vehicle or 200 mg/kg/day norfloxacin for one of three 10-day periods on GD 36-45, 71-80, or 111-120. There were no maternotoxic, embryotoxic, or fetotoxic effects observed. Plasma concentrations of norfloxacin in five cynomolgus monkeys following 50 and 200 mg/kg oral doses were not dose-proportionate. However, at a given dose, administered in cross-over fashion, plasma concentrations of norfloxacin were higher in nonpregnant females (approximately 20-40%) than during pregnancy when the same subject was compared. At the no-observed-effect dose for maternal and embryotoxicity (50 mg/kg), peak plasma concentrations of norfloxacin in pregnant cynomolgus monkeys are approximately threefold higher than those observed in human volunteers receiving norfloxacin at the maximum recommended therapeutic dose of 400 mg (5.7 mg/kg based on 70 kg body weight) twice per day.     

Stereoselective pharmacokinetics of RS-8359, a selective and reversible MAO-A inhibitor, by species-dependent drug-metabolizing enzymes

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine selectively and reversibly inhibits monoamine oxidase A (MAO-A). After oral administration of rac-RS-8359 to rats, mice, dogs, monkeys, and humans, plasma concentrations of the (R)-enantiomer were greatly higher than were those of the (S)-enantiomer in all species studied. The AUC((R)) to AUC((S)) ratios were 2.6 in rats, 3.8 in mice, 31 in dogs, and 238 in monkeys, and the (S)-enantiomer was almost negligible in human plasma. After intravenous administration of RS-8359 enantiomers to rats, the pharmacokinetic parameters showed that the (S)-enantiomer had a 2.7-fold greater total clearance (CL(t)) and a 70% shorter half-life (t(1/2)) than those for the (R)-enantiomer but had no difference in distribution volume (V(d)). No significant difference in the intestinal absorption rate was observed. The principal metabolites were the 2-keto form, possibly produced by aldehyde oxidase, the cis-diol form, and the 2-keto-cis-diol form produced by cytochrome P450 in rats, the cis-diol form in mice, RS-8359 glucuronide in dogs, and the 2-keto form in monkeys and humans. Thus, the rapid disappearance of the (S)-enantiomer from the plasma was thought to be due to the rapid metabolism of the (S)-enantiomer by different drug-metabolizing enzymes, depending on species.     

In vivo formation of hepoxilin A3 in the rat

Bolus intravenous injection of arachidonic acid (10 mg/kg) in the rat led to the appearance of hepoxilin A3 in the circulation. The product was assayed as the Me t-BDMSi derivative of its stable trihydroxy product trioxilin A3, by capillary gas chromatography-electron impact mass spectrometry using the stable deuterium isotope dilution technique. Hepoxilin A3, was undetected in blood samples taken prior to the injection of arachidonic acid, but rapidly appeared (4.62 +/- 1.3 ng/ml blood, n = 3) within 1 minute after injection of arachidonic acid. The plasma concentration of insulin increased by 36% over the same period after injection of arachidonic acid. These experiments demonstrate for the first time the formation of this new class of insulin secretagogues in vivo and their temporal correlation with plasma insulin concentrations in vivo.