Pharmacokinetics of buspirone following oral administration to rhesus monkeys.

Pharmacokinetics of buspirone and its active metabolite, 1-pyrimidinyl piperazine (1-PP) following oral administration were assessed in rhesus monkeys at doses used in chronic toxicology studies. The study was conducted over four periods in three male and three female rhesus monkeys. In the first three periods, buspirone hydrochloride solution was administered in a randomized manner by oral gavage at doses (expressed as buspirone free base) of 12.5, 25 and 50 mg kg(-1) once a day on days 1 and 7 and twice a day on days 2-6. In the last period, all monkeys received 25 mg kg(-1) buspirone as a single daily dose for 7 days. Serial plasma samples were collected for analysis of buspirone and 1-PP on days 1 and 7 in the first three periods and on day 7 in the last period for assessment of single dose and steady-state pharmacokinetics. Inter-animal variability in the pharmacokinetics of buspirone was high. Examination of Cmin vs time plots revealed that the steady state was attained by day 7 except for one monkey who demonstrated much higher Cmin values. For buspirone, dose proportionality was concluded for both Cmax and AUC on day 1 but not on day 7. The accumulation factor on day 7 for buspirone was nearly 5 for Cmax and 7 for AUC when compared with day 1. For 1-PP, dose proportionality was concluded except for Cmax in male monkeys on day 7. In contrast to buspirone, 1-PP showed less than 2-fold accumulation in Cmax and AUC values on day 7 compared with those on day 1. Exposure at a dose of 25 mg kg(-1) once daily was in between the 125 mg kg(-1) and 25 mg kg(-1) twice-a-day regimens. These results document dose-dependency in the steady-state pharmacokinetics of buspirone in rhesus monkeys.     

An abstinence syndrome following chronic administration of delta-9-tetrahydrocannabinol in rhesus monkeys

Chaired, chronically catheterized rhesus monkeys were administered IV delta-9-tetrahydrocannabinol (THC), 0.5 mg/kg every 6 h for 3 weeks. Following the first THC injection, the animals appeared heavy-lidded, immobile, and unresponsive to observation. Tolerance developed to these behaviors during the 3 weeks of THC administration, although the animals remained subdued compared to baseline. Following discontinuation of THC, animals showed an increase in gross movement, eye contact, and tooth baring of greater frequency and/or duration than observed before THC. This presumably represents a cannabis abstinence syndrome.     

Comparative pharmacokinetics of abecarnil in rat following single and multiple intragastric treatment and continuous administration via the diet.

The anxiolytic beta-carboline abecarnil was administered to female rats at doses of 10, 50, and 250 mg/kg/day for 4 weeks either intragastrically once a day or continuously via the feed. On days 1, 3, 7, 14, and 28, plasma level profiles (0-24 hr) and, additionally, on day 28, concentration profiles (0-24 hr) in liver, kidney, and brain were determined in identical groups of animals. Fecal excretion of unchanged abecarnil also was determined as a measure for enteric absorption. After both routes of administration, absorption was practically complete. Drug uptake via the feed resulted in a plateau-like plasma level without explicit maxima or minima. Indications were observed for a positive food intake plasma level correlation with lower plasma levels during the day and higher concentrations at night, for a slight increase of drug plasma levels during the 4-week period, and a dose-proportional increase of mean plasma concentrations. Intragastric treatment was characterized by clearly distinguishable absorption and disposition phases with prominent peaks after the 10 and 50 mg/kg doses, a plateau-like plasma level probably due to prolonged absorption after the 250 mg/kg dose, slight accumulation of drug in the plasma during continuous once-daily treatment, and a dose-proportional increase of the AUC. The drug load of the animals measured as concentrations in plasma and tissues was different after both routes of administration. Peak plasma levels were greater after intragastric treatment by a factor of 5, and the AUC was double compared to the feed experiment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intragastric agmatine on morphine-induced physiological dependence in beagle dogs and rhesus monkeys

Our previous studies demonstrated that subcutaneous injection of agmatine inhibits tolerance to and physiological dependence on morphine in mice and rats. In the present study we further evaluated the effects of intragastric (i.g.) administration of agmatine on morphine-induced physiological dependence in mice, rats, beagle dogs and rhesus monkeys. When agmatine (5-40 mg/kg, i.g.) was co-administered with morphine during the development of morphine-induced physiological dependence, it inhibited the abstinent syndrome precipitated by naloxone in mice, rats and beagle dogs. In addition, agmatine (40 mg/kg, i.g.) inhibited the abstinent syndrome precipitated by naloxone in mice when it was administered on the test day. In naloxone precipitated and naturally abstinent morphine dependent model in rhesus monkeys, agmatine (40 or 80 mg/kg, i.g.) inhibited the development of physiological dependence when it was co-administered with morphine. After the development of morphine dependence, agmatine (80 mg/kg, i.g.) inhibited the naturally abstinent syndrome during the 7-d abstinent period. All these results suggested that intragastric administration of agmatine inhibits morphine-induced physiological dependence in animal models.     

Absorption and metabolism of capsaicinoids following intragastric administration in rats

Summary This study was performed to examine the metabolism and absorption of intragastrically administered capsaicinoids in the anaesthetized rat.[³H]-dihydrocapsaicin ([³H]-DHC) and unlabelled capsaicin were readily absorbed from the gastrointestinal tract but were almost completely metabolized before reaching the general circulation. A certain degree of biotransformation already took place in the intestinal lumen. Unchanged compounds (identified by chromatography) were present in portal vein blood. There seems to be a saturable absorption and degradation process in the gastrointestinal tract and a very effective metabolism in the liver.Less than 5% of the total amount of extracted radioactivity consisted of unchanged [³H]-DHC in trunk blood and brain 15 min after gastrointestinal application. On the other hand, approximately 50% unchanged [³H]-DHC was detected in these tissues 3 min after i.v. or 90 min after s.c. application of the capsaicinoids. Dihydrocapsaicin (DHC) or [³H]-DHC were metabolized when incubated in vitro with liver tissue but not with brain tissue. The metabolic product(s) did not show capsaicin-like biological activity.It can be concluded that rapid hepatic metabolization limits systemic pharmacological effects of enterally absorbed capsaicin. Send offprint requests to J. Donnerer at the above address     

Naltrexone metabolism and sustained release following administration of an insoluble complex to rhesus monkeys and guinea-pigs

Both the release and the metabolism of naltrexone have been evaluated after intramuscular administration of a sustained release [15,16-3H2]naltrexone aluminium tannate complex in guinea-pigs and rhesus monkeys. In both species, measurable excretion of radioactivity was obtained for greater than 50 days and complete recovery of the dose was obtained in the guinea-pig. The radioactivity excretion rate-time profile differed in the two species with guinea-pig yielding a continuously declining rate and monkey yielding a peak at 5 days. In selected monkey urine samples (days 4, 17-20 and 49-52) subjected to t.l.c., evidence was obtained for the presence of naltrexone, beta-naltrexol and 2-hydroxy-3-O-methyl-beta-naltrexol, mostly as glucuronide and/or sulphate conjugates. The t.l.c. data also suggest that in monkey a naltrexone metabolite builds up relative to naltrexone over the 52 day release period.     

Liver function studies on rhesus monkeys (Macaca mulatta) following the administration of hydrazine sulfate

Hydrazine sulfate (Hs), a known occupational toxin and putative cancer therapeutic agent, was administered iv at various doses to rhesus monkeys in an effort to measure its effects upon the liver. Function tests included indocyanine clearance (ICG Vmax and Km), serum bile acid levels and serum enzyme activities, including alanine aminotransferase, gamma glutamyl transferase, and a panel of 19 other blood chemical constituents. Hepatic function and other biochemical tests were generally within the normal range following single-dose Hs administration (10-40 mg/kg) and did not suggest the presence of significant liver injury. Two monkeys receiving 80 mg/kg Hs exhibited extensive hepatic lipidosis without biochemical or histologic signs of necrosis. Hs, administered iv, appears to produce little or no hepatic toxicity.     

猕猴硬膜外及静脉注射 [~(125)I]虎纹毒素-1的药代动力学(英文)

目的　研究与比较猕猴硬膜外 (ed)及静脉 (iv)注射虎纹毒素 1后的药代动力学过程。方法　Iodogen法标记虎纹毒素 1 ,按 0 388MBq·kg- 1 的剂量向猕猴第 3和第 4腰椎之间硬膜外腔及静脉注射标记后虎纹毒素 1 ,用反相高效液相色谱检测猴血清中的药物放射性活度 ;γ 计数仪检测猴第 3和第 4腰椎硬膜外腔的药物放射性活度。结果　制备了具有生物活性的 [1 2 5I]虎纹毒素 1。硬膜外给药 1 0min后 ,给药部位局部硬膜外腔的药物放射性占总给药量的0 38,说明硬膜外给药是成功的 .硬膜外及静脉给药后 ,血药浓度分别在 30min和 2min达峰 ,分别为 (0 70± 0 0 4 )MBq·L- 1 和 (4 98± 0 58)MBq·L- 1 。两种给药途径的药时曲线不同 :猕猴硬膜外和静脉给药后 ,末端T12 分别为(1 0 36± 0 2 7)h和 (1 1 0 3± 1 1 6)h ;ClS 分别为 (1 2 9±0 0 7)L·h- 1 ·kg- 1 和 (1 2 5± 0 2 3)L·h- 1 ·kg- 1 ,硬膜外给予 [1 2 5I]HWTX 1的绝对生物利用度 (95± 5) %。结论　硬膜外和静脉两种给药方式下 ,[1 2 5I]虎纹毒素 1在猕猴体内的药代动力学过程具有差异性 ,两种给药方式下 [1 2 5I]在猕猴体内的分布与吸收特点对于虎纹毒素 I的临床药效学和毒理学研究提供了参考数据。     

Self administration of heroin and cocaine in morphine-dependent and morphine-withdrawn rhesus monkeys

Rationale  Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking. Objective  This study examined how chronic morphine administration or withdrawal modified self administration of heroin or cocaine. Methods  Four monkeys responded under a fixed ratio 10 schedule to receive i.v. infusions of heroin (0.56–560 μg/kg/infusion) or cocaine (1–100 μg/kg/infusion). Monkeys received morphine twice daily; the final dose was 10 mg/kg/12 h. Dose–effect curves for heroin or cocaine were determined in 150-min sessions throughout morphine administration and during temporary suspension when withdrawal signs were also monitored. Heroin dose–effect curves and withdrawal signs were determined daily following termination of morphine administration. Results  Before monkeys received morphine, heroin, and cocaine maintained responding with unit doses of 1.78 μg/kg of heroin and 10 μg/kg/injection of cocaine resulting in, on average, 13.4 and 20.8 infusions, respectively. When monkeys received morphine daily, self administration of heroin and cocaine decreased to, on average, 3.1 and 11.3 infusions, respectively. Responding for heroin or cocaine recovered following temporary (17–53 h) suspension of morphine administration. The number of heroin infusions and total withdrawal signs increased when morphine administration was terminated. Withdrawal signs peaked 3–4 days after morphine; however, the number of infusions remained elevated for 8 weeks. Conclusions  Changes in self administration responding did not precisely covary with signs of withdrawal and responding for small doses of heroin persisted long after discontinuation of morphine, suggesting that non-pharmacologic (e.g., conditioned reinforcing) effects might contribute to the maintenance of lever pressing under these conditions. This work was supported by United States Public Health Service Grant DA05018 and Senior Scientist Award K05 DA17918 (CPF).     

Guanethidine induced sympathectomy in the adult rat. I. Functional effects following subacute administration

Guanethidine sulphate 5 and 40 mg/kg was administered intraperitoneally to adult rats for 4, 8, 14, and 28 days followed by discontinuation for 1 day, after administration for 28 days and additionally for 8, 14, 29, and 60 days. Under chloralose-urethane anaesthesia the mean arterial blood pressure and the mean heart rate were determined and the response of these parameters to intravenous noradrenaline 3-1600 ng was recorded. The blood pressure was not significantly changed after guanethidine 5 mg/kg, but lowered by 40 mg/kg, the decrease being reversible on discontinuation. The response of both parameters to noradrenaline was increased by guanethidine depending on the dose. The hypersensitivity was partly reversible on discontinuation, but a significantly increased sensitivity of the heart rate to noradrenaline was observed 60 days after discontinuation of guanethidine 40 mg/kg for 28 days. Histologically a profound loss of nerve cells of the superior cervical ganglion was observed following guanethidine 40 mg/kg, whereas no change was observed after 5 mg/kg. The present investigation has demonstrated that guanethidine 5 mg/kg does not induce histological or permanent haemodynamic changes, whereas 40 mg/kg for 28 days result in an incomplete sympathectomy accompanied by a partially irreversible hypersensitivity to noradrenaline. There is no simple relation between the loss of ganglion cells and the haemodynamic changes, and hence the hypersensitivity to noradrenaline is only in part due to the destruction of the postganglionic sympathetic neurone obtained by long term administration of large doses of guanethidine.     

Renal binding of cadmium in the rat following intragastric exposure

Renal binding of cadmium was compared in groups of rats administered cadmium intragastrically or subcutaneously in doses resulting in similar renal cadmium concentrations. In rats administered cadmium intragastrically the renal concentrations of copper and metallothionein were lower, suggesting disturbance in copper metabolism. These changes were alleviated gradually in the post-exposure period. In experiments with 64Cu it has been shown that intragastric exposure to cadmium reduced copper absorption to about 21% of that in the control rats, thus explaining the poor copper availability for renal binding of cadmium in the form of Cd,Cu-metallothionein. Changes in zinc uptake were less strongly marked and were limited to slight decrease of zinc content in the kidneys.     

Vaginal drug absorption in rhesus monkeys I: development of methodology.

Earlier reports from these laboratories described a procedure for determining vaginal drug absorption in the rabbit based upon a perfusion system, and data on the vaginal absorption of the straight-chain aliphatic alcohols and carboxylic acids were given. These studies have been extended to the rhesus monkey. Rib-cage-type cells were designed for intravaginal insertion through the vulval orifice and to fit the specific dimensions of the monkey vagina. The general design of the cell was similar to that used in the rabbit vaginal absorption studies. The persusion system was checked by using 3H-polyethylene glycol 4000, and no significant leaks from the cell were found. The absorption of the alcohols followed first-order kinetics. The computed apparent permeability coefficients for the alcohols were of comparable magnitude to those previously reported for the rabbit vaginal membrane.     

Mephenytoin stereoselective elimination in the rat: I. Enantiomeric disposition following intravenous administration

The stereoselective disposition of mephenytoin was characterized after an intravenous bolus dose of racemic mephenytoin to rats being infused with 50% polyethylene glycol 400/50% saline via the jugular and hepatic portal vein. No significant influence on mephenytoin disposition was noted due to the site selected for the administration of the 50% polyethylene glycol 400 solution. The mean (+/- SD) clearance of R- and S-mephenytoin were 171 +/- 58 ml/hr (R) and 110 +/- 37 ml/hr (S), and the mean (+/- SD) volumes of distribution were 325 +/- 75 ml (R) and 359 +/- 72 ml (S). The clearance of R-mephenytoin was significantly larger than the clearance of S-mephenytoin, but this stereoselective difference is of opposite stereochemistry and of much smaller magnitude than the stereoselective difference reported for these enantiomers in man. The difference in the volumes of distribution of R- and S-mephenytoin was not significant.     

Toxicology studies of linear alkylbenzene sulphonate (LAS) in rhesus monkeys. I. Simultaneous oral and subcutaneous administration for 28 days.

A toxicological investigation was performed with the linear alkylbenzene sulphonate (LAS) using 4 groups of 3 male and 3 female monkeys. Dosages were 0, 30, 150, 300 and 0, 0.1, 0.5, 1.0 mg/kg/day by simultaneous oral (p.o.) and subcutaneous (s.c.) administration respectively, for 28 days. At 300 p.o. and 1.0 s.c. mg/kg/day, the monkeys vomited frequently and usually within 3 hours of administration. An increased frequency of loose or liquid faeces was recorded for animals receiving 150 p.o. and 0.5 s.c. and 300 p.o. and 1.0 s.c. mg/kg/day. Fibrosis of the injection sites was found among all the test groups, the incidence and severity being dose related. Ophthalmoscopy, laboratory examination of blood and urine, organ-weight analysis and histopathological investigation did not detect any further treatment related responses. Previous reports concerning oral administration of tetrapropylene benzene sulphonates (ABS) to dogs record prompt emesis ascribed to local gastro-intestinal effects. Vomiting observed during this investigation was considered to be of possible central origin.     

Pharmacokinetics of diclofenac sodium after intramuscular administration in combination with triamcinolone acetate

Summary Seventy-five mg diclofenac sodium were given intramuscularly to 15 subjects alone and in combination with 40 mg triamicinolone acetate. Plasma levels of diclofenac were measured and pharmacokinetic parameters were calculated. The results indicate no statistically significant differences for most of the parameters. The maximum plasma concentrations (Cp_max) was increased by about 20% in combination with the glucocorticoid, whereas terminal elimination rate did not change significantly.     

Disposition and pharmacokinetics of naltrexone after intravenous and oral administration in rhesus monkeys

The purposes of this investigation were to determine the disposition of naltrexone (NTX) in monkeys and assess the role of first-pass metabolism and enterohepatic cycling in the disposition process. Concentrations of naltrexone and three metabolites were determined in plasma and urine as a function of time after po and iv NTX administration in six monkeys. Urinary recovery of NTX and metabolites 0-48 hr after iv administration (10 mg/kg) totaled 52% of the dose. Recovery in feces was minimal. Total urinary excretion of NTX and metabolites after po administration was 89% of that after iv administration, suggestive of good absorption of NTX from solution. However, the area under the plasma level-time curve for NTX after po administration was only 3.6% of that after iv administration, indicating a very high first-pass effect. The calculated extraction ratio was 0.96-0.99. Analysis of plasma level-time and urinary excretion rate-time data for NTX, conjugated NTX, beta-naltrexol, and conjugated beta-naltrexol after iv administration revealed that 1) the decline of plasma levels or urinary excretion rates with time for the conjugated metabolites was parallel to the decline for the apparent precursor; 2) the decline of plasma levels or urinary excretion rates for beta-naltrexol was slower than for naltrexone; and 3) there is evidence for a pronounced enterohepatic cycling of conjugated NTX and conjugated beta-naltrexol that influences the plasma level-time profile of these conjugates and the unconjugated compounds as well.     

Inhibiting effect of ethinylestradiol/levonorgestrel combination on microsomal enzymatic activities in rat liver and kidney.

The aim of the study was to evaluate the effects of two therapeutic combinations of ethinylestradiol (EE) and levonorgestrel (LE), which are used in triphasic contraceptives, on the activities of drug-metabolizing enzymes in rat liver and kidney. Sexually mature female Wistar rats were given 0.03 mg EE and 0.05 mg LE, or 0.03 mg EE and 0.125 mg LE for 6 or 18 sexual cycles, i.e. for 30 or 90 days. EE/LE inhibited not only the metabolic capacity of P450, a protein which directly undergoes suicide inhibition, but also the level of rat liver cytochrome b5 (dependent on the heme pool) as well as the activities of NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase in the liver and kidney. The majority of these effects were independent of the gestagen dose and of the duration of treatment, suggesting that estrogen is a predominant inhibiting factor in the EE/LE combination. The study has revealed differences in the enzyme activities between the liver and kidney, which may result from the fact that these organs display different sets of P450 isoforms and, therefore, their monooxygenase systems show distinct capacities to metabolize exogenous steroids.     

Metabolism of norethisterone and norethisterone derivatives in rat uterus, vagina, and aorta.

The 19-nor-progestogen norethisterone is used as a progestogen component in contraceptives and in continuous- and sequential combined hormone replacement therapy (HRT) in postmenopausal women. Metabolism of norethisterone in HRT target tissues may play a role in its biological response. The aim of this study was to investigate which steroid-metabolizing enzymes are present in rat uterus, vagina, and aorta, three HRT target tissues. Next, the ability of the tissues to metabolize norethisterone was assessed. Furthermore, to investigate the effect of substituents at the 7- and 11-position, the metabolism of Org OM38 (7alpha-methyl-norethisterone), Org 4060 (11beta-ethyl-norethisterone), and Org 34694 (7alpha-methyl,11-ethylidene-norethisterone) was studied. Using radiolabeled progesterone, the presence of 20alpha-hydroxysteroid dehydrogenase, 5alpha-reductase, and 3alpha-hydroxysteroid dehydrogenase activity could be demonstrated in uterus, vagina, and to a lesser extent in aorta. The combined action of the latter two enzyme activities resulted in 3alpha-OH,5alpha-H-norethisterone as the major metabolite of radiolabeled norethisterone in uterus (26.9%), vagina (37.1%), and aorta (1.4%). The norethisterone derivatives, however, were metabolized to a much lesser extent (1.0-7.6%). No formation of 5alpha-reduced forms of Org 4060, Org OM38, or Org 34694 was found, while formation of minor amounts of 3alpha-OH-Org 4060 and 3alpha-OH-Org OM38 could be demonstrated in both uterus, vagina, and aorta. These findings confirm the role of 5alpha-reductase as a rate-limiting step in the metabolism of norethisterone derivatives and show important inhibitory effects of substituents at the 7alpha- and 11-position of the steroid skeleton on 5alpha-reduction.