Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats.

1. The purpose of this investigation was to examine in vivo drug-concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose. 2. Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg-1. The pharmacokinetics could be described by an open 2-compartment pharmacokinetic model. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of clearance and volume of distribution were 28 +/- 2 ml min-1 kg-1 and 2.6 +/- 0.31 kg-1, respectively, and were not significantly different from the values obtained at the other doses. 3. The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose-dependent elevations of the seizure threshold were observed. 4. By pharmacokinetic-pharmacodynamic modelling, a log-linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (Cmin) were 243 +/- 27 microA and 0.11 +/- 0.02 mg l-1, respectively and not significantly different from the values obtained at the other doses. 5. In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter-animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra-animal variability was 24 +/- 18%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic-pharmacodynamic modelling of the interaction between flumazenil and midazolam in volunteers by aperiodic EEG analysis

The CNS effects resulting from the combined administration of midazolam and flumazenil were studied in 8 healthy volunteers to develop a model of the pharmacokinetic-pharmacodynamic interaction. Electroencephalograms (EEG) were recorded between Fp1-M1 and Fp2-M2. The EEG parameter total number of waves between 12 and 30 Hz (TNW12-30) derived by aperiodic analysis was used to quantify the effect. Following a 15 min baseline EEG recording, infusion of placebo or flumazenil was started. Infusion regimens for flumazenil were designed so that 'steady-state' concentrations of 10 and 20 micrograms/L were obtained. Doses of midazolam 15, 30 and 60 mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 micrograms/L (session B) or 20 micrograms/L (session C), respectively. Venous blood samples were taken until 8 h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (Emax) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (Cem) [Cem/Kp] and TNW12-30. Within 2 to 5 min of starting the midazolam infusion all subjects fell asleep, with loss of eyelid reflex. They awoke between 25 and 82 min later in all 3 sessions. The mean (+/- SD) plasma drug concentrations of midazolam corresponding to half the maximum increase in TNW12-30 (EC50) were 276 +/- 64, 624 +/- 187 and 1086 +/- 379 micrograms/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t1/2ke0), estimated by a nonparametric method, were 2.2 +/- 1.2, 3.3 +/- 3.3 and 2.9 +/- 1.2 min for the 3 different sessions. Emax and N were not affected by flumazenil. In each subject the plot of the average measured steady-state plasma flumazenil concentration versus the EC50 of midazolam showed a linear relationship. The plasma concentration of flumazenil that doubled the EC50 of midazolam (Cf,2) was 6.5 +/- 1.0 micrograms/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.     

Pharmacokinetic-pharmacodynamic modelling of the EEG effect of alfentanil in rats: assessment of rapid functional adaptation

1. The purpose of the present investigation was to quantify rapid functional adaptation in the concentration-pharmacological effect relationship of alfentanil in rats using quantitative EEG parameters as a pharmacodynamic endpoint. Three groups of 6–7 rats received in a randomized fashion two consecutive infusions of 2.00, 3.14, or 4.24 mg/kg⁻¹ of alfentanil in 20, 40 or 60 min, respectively. The EEG was continuously recorded and frequent arterial blood samples were collected for determination of the alfentanil concentration by gas chromatography.
2. The pharmacokinetics of alfentanil were most adequately described by a bi-exponential function. The values (mean±s.e., n=20) of clearance, volume of distribution at steady-state and terminal half-life were 45±3 ml.min⁻¹.kg⁻¹, 0.91±0.09 l/kg⁻¹ and 23±1 min, respectively, and independent of the administered dose.
3. Increase in power in the 0.5–4.5 Hz (delta) frequency band of the EEG was used as the measure of the pharmacological response. By pharmacokinetic-pharmacodynamic modeling the individual concentration-EEG effect relationships of alfentanil were derived which were successfully quantified by the sigmoidal E_max pharmacodynamic model. When the results of the first of the two consecutive infusions were compared, no systematic differences in the pharmacodynamic parameters were observed for the different infusion rates. The averaged values of the pharmacodynamic parameters of alfentanil were (mean±s.e., n=20): E₀=56±3 μV, E_max=93±8 μV, EC₅₀=235±27 ng.ml⁻¹ and Hill factor=1.6±0.1, respectively. For the second of the two consecutive infusions a significantly higher value of the EC₅₀ of 404±56 ng.ml⁻¹ was observed (P<0.05), while the values of the other pharmacodynamic parameters were unchanged. Simulations according to a mechanism-based model indicated that the observed change in concentration effect relationship can be explained by a 40% loss of functional μ-opioid receptors.
4. The results of the present study show that upon the administration of a single intravenous dose, acute functional adaptation does not interfere with the assessment of the concentration-EEG effect relationship of alfentanil. Upon repeated administration however functional adaptation may be a complicating factor.

     

八位中国男性咪达唑仑脑电效应的药物动力学-药效学模型(英文)

本文分析了8位中国健康男性血清咪达唑仑浓度-脑电效应的定量关系,采用12—30Hz之间的每秒总波数(TNW_(12—30))作为脑电效应指标。由药物动力学-药效学软件所计算的药效学参数为:T_2~1_(keo)=1.3±0.9min~(-1),EC_(50)=254±54μg·L~(-1),N=2.9±0.6。实验证明了由脑电分析得出的参数TNW_(12—30)可用于浓度-效应关系的研究。     

Pharmacokinetic-pharmacodynamic modelling in the early development phase of anti-psychotics: a comparison of the effects of clozapine, S 16924 and S 18327 in the EEG model in rats

1. The use of pharmacokinetic/pharmacodynamic (PK/PD) analysis in early compound development was investigated in the rat for two developmental anti-psychotic compounds with clozapine as a positive control. 2. Three plasma samples were collected from each of eight animals according to a pre-defined sampling matrix allowing a total of 12 time points for PK analysis. Quantitative electroencephalography (QEEG), particularly the theta and beta frequencies, was used as a measurement of pharmacological effect. 3. PK/KD modelling of the sparse PK data available relative to a rich set of PD data was achieved using a population approach in NONMEM (IV). Individual PK parameter estimates were incorporated into a PK/PD model. 4. Qualitative EEG changes in rat and human were similar for clozapine, but different for the two developmental compounds, suggesting that changes in these PD parameters may not be specifically related to the anti-psychotic activity. 5. Although no definitive data are available concerning the signal specificity of EEG frequency bands with respect to dopaminergic or serotonergic receptor activity, qualitative and quantitative differences seen in EEG parameters are likely to result from the multiple receptor occupancy for these compounds. 6. The results confirm the value of population PK/PD modelling in conjunction with sparse sampling to enable determination of concentration effect relationships in the pre-clinical development programme of CNS-active drugs.     

Pharmacokinetic-pharmacodynamic modelling of tiagabine CNS effects upon chronic treatment in rats: lack of change in concentration-EEG effect relationship.

The pharmacodynamics of the gamma-aminobutyric acid (GABA) uptake inhibitor (R)-N-(4,4-di-(methylthien-2-yl)but-3-enyl) nipecotic acid (tiagabine) was quantified in rats following chronic (14 days) administration by an integrated pharmacokinetic-pharmacodynamic (PK/PD) modelling approach. The increase in beta activity (11.5-30 Hz) of the EEG as derived by fast Fourier transformation analysis was used as pharmacodynamic endpoint. Two groups of male Wistar rats were treated for 14 days with either tiagabine at a steady-state concentration of 198+/-10 ng ml(-1) or placebo. Chronic treatment with tiagabine resulted in an increase of the EEG effect parameter by 38+/-2 microV. In the PK/PD experiment the time course of the EEG effect was determined in conjunction with the decline of drug concentrations after an i.v. bolus administration of 10 mg kg(-1). The pharmacokinetics of tiagabine was most adequately described by a bi-exponential function. No influence of chronic treatment on the pharmacokinetics was observed. Hysteresis between plasma concentration and EEG effect was accounted for by incorporation of an 'effect-compartment' in the model. The observed relationship between tiagabine concentrations and EEG effect was non-linear and described on the basis of the Hill equation. Between the treatment groups no differences in the pharmacodynamic parameters were observed. The population means for the different pharmacodynamic parameters were: maximum EEG effect 82 microV, EC(50) 486 ng ml(-1), Hill factor 2.0 and k(e0) 0.060 min(-1). In the in vitro [(3)H]GABA uptake assay no changes in affinity or functionality for the GABA uptake transporter were observed, consistent with the absence of adaptation. It is concluded that chronic treatment with tiagabine in an effective dose range for 14 days does not produce functional adaptation to tiagabine-induced GABA-ergic inhibition in vivo.     

The influence of midazolam on active avoidance retrieval and acquisition rate in rats

The purpose of the present study was to examine the influence of midazolam on the retrieval and acquisition rate of two-way active avoidance in rats. In the schedule 2 x 100 trials, the effects of midazolam (0.5-5.0 mg/kg), benzodiazepine binding site antagonist flumazenil (2.5-10.0 mg/kg), specific antagonist of GABA(A) receptor, bicuculline (0.5-4.0 mg/kg), and the blocker of GABA(A) receptor containing Cl(-) channels, picrotoxin (1.0-5.0 mg/kg), on the second day retrieval of avoidance performance were investigated, as well as the influence of the used blockers of GABA(A) receptor function on midazolam effects. Furthermore, the effect of midazolam (1.0 mg/kg) on acquisition rate in the 5 x 50 schedule, as well as the effects of third day treatment changing in that paradigm, was examined. Throughout the study, drugs were given intraperitoneally, 30 min before testing. Midazolam at the dose of 1.0 mg/kg facilitated avoidance retrieval, whereas flumazenil and bicuculline did not significantly change behavior. Picrotoxin (5.0 mg/kg) diminished performance. All three kinds of blockers used abolished facilitatory action of midazolam, confirming GABAergic mediation of the effect of benzodiazepine. Midazolam (1.0 mg/kg) increased acquisition rate during five consecutive days relative to saline, but without significant effect on the first day acquisition. In the case of third day changing of treatments, the intersection of regression rate lines was detected. Results from active avoidance paradigm experimentally support the findings from human studies that in certain circumstances, benzodiazepines, potentiating GABAergic neurotransmission, could produce retrieval-enhancing effects in memory tasks.     

The influence of route of administration on the acute cardiovascular effects of cocaine in conscious unrestrained pregnant rats

The intravenous route of administration, accessed via a subcutaneous vascular access port, has been recently suggested as an animal model for studying the developmental effects of maternal cocaine abuse in the pregnant and/or group-housed rat. The present study (1) assessed the cardiovascular effects of intravenous (IV) cocaine, delivered via bolus injection, in chronically catheterized near-term pregnant rats, and (2) compared the IV cardiovascular responses to those following cocaine delivered via the commonly employed subcutaneous (SC) and intragastric (IG) routes of administration. Pregnant gestation day 15 (GD15) young adult female Sprague-Dawley rats (n = 21) were anesthetized and catheters surgically implanted into the carotid artery, jugular vein, fundus of the stomach, and a subcutaneous pouch. On GD17-19, heart rate (HR) and mean arterial pressure (MAP) were assessed, using a within-subjects design, prior and subsequent to IV (3 mg/kg), IG (60 mg/kg), and SC (40 mg/kg) cocaine. An interval of 6 h separated IV and IG cocaine administration and an interval of 18 h separated IG and SC cocaine administration. The peak responses of HR (23% downward arrow) and MAP (37% upward arrow) following IV cocaine were noted within 0.5 min. In contrast, the peak responses of HR (4% downward arrow, 6% downward arrow) and MAP (2% upward arrow, 15% downward arrow) after IG (23 min) or SC (26 min) cocaine, respectively, were significantly smaller and markedly delayed. No significant change in aortic blood flow velocity was detected following cocaine via any route of administration, although phasic flow velocities (PFV) were differentially sensitive to route of administration (PFV(dias) not PFV(sys)); IV cocaine increased (55% upward arrow) whereas IG or SC cocaine decreased approximately 35% downward arrow) PFV(dias). The pressor effects of an equimolar dose of IV cocaine methiodide (3.9 mg/kg) were indistinguishable from those of IV cocaine (38% upward arrow vs. 37% upward arrow), as were the effects on PFV(dias) (83% upward arrow vs. 55% upward arrow). The lack of an effect of cocaine methiodide on HR was consistent with the bradycardia effect of cocaine attributable to central mediation of the baroreflex. Finally, the pressor effects of IV cocaine paralleled the rapidly peaking arterial plasma levels of cocaine noted within 30 s after the initiation of drug injection. In sum, prominent effects of IV cocaine on maternal cardiovascular physiology are noted; as such, the recent reports of a lack of maternal/fetal toxicity following daily (3-6mg/kg) IV cocaine during GD8-21 are not due to use of an ineffective drug dose. It was equally clear that the SC and IG routes of exposure did not reproduce the cardiovascular component(s) of the expected physiological response to cocaine.     

Pharmacokinetic-pharmacodynamic modelling of the convulsant interaction between norfloxacin and biphenyl acetic acid in rats

Fluoroquinolones (FQs) are associated with a low incidence of central nervous system (CNS) side effects, possibly leading to convulsions, especially when co-administered with nonsteroidal anti-inflammatory drugs (NSAIDS). Although the in vivo pro-convulsant activity of NSAIDS is essentially unknown, the convulsant potential of FQs is traditionally evaluated by in vitro gamma-aminobutyric acid (GABA) binding experiments in the presence of 4-biphenyl acetic acid (BPAA), the active metabolite of fenbufen. The aim of this study was therefore to investigate the BPAA-norfloxacin convulsant interaction in vivo. Male Sprague-Dawley rats (n = 27) were given BPAA orally, at various doses 1 h before norfloxacin infusion, which was maintained until the onset of maximal seizures, when cerebrospinal fluid (CSF) and plasma samples were collected for analysis. An inhibitory E(max) effect model with a baseline effect parameter was fitted to the norfloxacin versus BPAA concentrations in the CSF, previously shown to be part of the biophase. This model includes three parameters: the concentrations of norfloxacin in the absence of BPAA (C(CSF0, Nor)), and when BPAA concentration tends toward infinity (C(CSFbase, Nor)), and the BPAA concentration for which half of the maximal effect is observed (C(CSF50, BPAA)). The maximal proconvulsant effect of BPAA is given by the C(CSF0, Nor) / C(CSFbase, Nor) ratio, estimated to approximately 6 in this study. Derived models were developed in plasma to account for the non-linear CSF diffusion of norfloxacin and protein binding of BPAA. In conclusion this study has shown that the convulsant interaction between norfloxacin and BPAA in rats, can be adequately characterized by modelling of the CSF concentrations of the two drugs at the onset of activity, following their administration in various proportions.     

Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers. Pharmacokinetic/pharmacodynamic modelling

The effects of midazolam on the EEG were related to plasma midazolam concentrations in 8 healthy male volunteers in order to develop a pharmacokinetic-pharmacodynamic model. The EEG parameters were derived by aperiodic analysis. The EEG was recorded between Fp1-M1 and Fp2-M2. Following a 15-minute baseline EEG registration, midazolam 15 mg was given intravenously over 5 minutes. Venous blood samples were taken until 8 hours after the start of the infusion. Within 2 to 4 minutes of starting the infusion all subjects became asleep, with loss of eyelid reflex. The most obvious EEG changes, in the beta frequency range (12 to 30 Hz), were observed within 2 minutes of the start of drug administration. Seven subjects awoke 60 to 70 minutes after the start of the infusion and 1 awoke after 45 minutes. The EEG parameter that best characterised the effect of midazolam was the total number of waves per second in the frequency range 12 to 30 Hz (TNW12-30). This was used as the effect parameter in the pharmacokinetic-pharmacodynamic modelling. The plasma concentration-time data were characterised by a triexponential function for all subjects. To allow for a possible delay between plasma midazolam concentration and EEG effect, a hypothetical effect compartment was included in the pharmacokinetic-pharmacodynamic model. A sigmoid maximum effect (Emax) model was used to characterise the effect compartment midazolam concentration-TNW12-30 data. The plasma drug concentration corresponding to half the maximum increase in TNW12-30 (EC50) was 290 +/- 98 micrograms/L.(ABSTRACT TRUNCATED AT 250 WORDS)     

Drug metabolite concentration-time profiles: influence of route of drug administration.

In order to assess the contribution of an active metabolite to the overall pharmacological response following drug administration it is necessary to characterise the metabolite concentration-time profile. The influence of route of drug administration on metabolite kinetics has been investigated by computer simulation. Comparisons between simulated profiles and published concentration-time data have been carried out. A route dependence in metabolite concentration-time curves is readily apparent provided the metabolite kinetics are formation rate limited and the hepatic clearance of drug is greater than 25 l/h (medium to highly cleared). Oral drug administration produces a triphasic metabolite concentration-time profile whereas only two phases are discernable after intravenous drug administration. The magnitude of the difference in maximum metabolite concentration is directly proportional to the hepatic clearance of drug due to first-pass metabolite production. The route dependence in the shape of the metabolite concentration-time curves is most dramatic when the absorption and distribution of drug and the elimination of metabolite is rapid. A reduction in the rate of either of these processes alters the shape of the metabolite concentration-time profile such that the consequence of first-pass metabolite formation may be reduced.     

Kinetics of aluminum in rats. III: Effect of route of administration.

Male Fischer rats received 0.1 mg/kg (bolus) of elemental aluminum as the sulfate salt via the portal (n = 4) or systemic (n = 4) route of administration. Blood and bile were serially sampled over an 8-h period, postadministration. Aluminum was determined by flameless atomic absorption spectrophotometry. Blood aluminum concentrations declined in a monoexponential fashion, with half-lives of 0.7 h (portal) and 1.08 h (systemic) (p less than 0.05). The corresponding systemic clearances were 48.9 +/- 10.6 and 35.1 +/- 3.64 mL/(h.kg) (p less than 0.05). The systemic availability following portal administration was 0.66, indicating a significant "first-pass" effect. Biliary aluminum recovery (% dose) was negligible following both routes [0.83 +/- 0.062% (portal) versus 1.3 +/- 0.22% (systemic), p less than 0.05]. Bile flow decreased approximately 40% (p less than 0.05) immediately upon injection of aluminum via the portal route only; flow remained suppressed throughout the study. This decrease in bile flow was most likely responsible for the lower biliary recovery with this route. In contrast, liver recovery of aluminum at 8-h postadministration was higher with the portal route (65.4 +/- 4.1 versus 39.4 +/- 2.52%). These results show that reported values for oral "bioavailability" of aluminum, often calculated by the standard AUC ratio method, underestimate the true extent of absorption. One mechanism of aluminum-related jaundice observed clinically may be due to cholestasis.     

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam

Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC_0–3, AUC_0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (C_max) 2- to 2.5-fold compared with placebo. The AUC_0–3 and the C_max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole. Received: 1 July 1996 / Accepted in revised form: 4 September 1996     

Pharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. a minireview

Abstract: Pain is characterized by its multi‐dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state‐of‐the‐art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD of analgesics. For the so‐called weak opioids such as codeine, experimental human studies showed that analgesia relies mainly upon biotransformation into morphine. However, the time‐course of plasma concentrations of morphine did not always reflect the time‐course of effects, the major site of action being the central nervous system. For tramadol, a correlation has been observed between the analgesic response and the PK of the (+)R‐O‐demethyl‐tramadol metabolite. For ‘stronger’ opioids such as oxycodone, studies assessing the PK/PD of oxycodone suggested that active metabolite oxymorphone also strongly contributes to the analgesia and that analgesia may also be partially related through an action to peripherally located κ‐opioid receptors. Different models have been proposed to describe the time‐course of buprenorphine. An effect‐compartment model was adopted to describe the PK/PD of morphine and its active metabolite, morphine‐6‐glucuronide (M6G). A longer blood‐effect site equilibration half‐life t_1/2k_e0 was observed for M6G, suggesting a longer onset of action. The studies assessing the PK/PD of fentanyl and its derivatives showed a short t_1/2k_e0 for analgesia, between 0.2 and 9 min., reflecting a short onset of effect. In conclusion, depending on the speed of transfer between the plasma and the effect site as well as the participation of active metabolites, the time‐course of the analgesic effects can be close to the plasma concentrations (alfentanil and derivates) or observed with a prolonged delay (codeine, buprenorphine, morphine). These PK/PD data can be used to better characterize the differences between opioids, and partly explain the important observed variability among opioids in experimental conditions and should be systematically evaluated during drug development to better predict their selection in specific clinical conditions.     

Behavioral effects of chronic buspirone administration in the pigeon: comparison to midazolam

The effects of acute and chronic administration of buspirone and midazolam were examined in White Carneau pigeons (N = 5) responding under a fixed-ratio 30 (FR 30) schedule of food presentation. Each drug was studied in all pigeons. For three pigeons, buspirone was studied before midazolam, while the order was reversed for the other two subjects. For each drug, a dose-response curve was determined before (prechronic) and two weeks after (postchronic) discontinuation of chronic administration. Prior to chronic drug administration, buspirone (0.3-5.6 mg/kg) and midazolam (0.1-3.0 mg/kg) decreased response rates in all subjects, in a dose-dependent manner. Midazolam was more potent than buspirone; midazolam's ED50 (95% C.I.) was 0.53 (0.41-0.69) mg/kg compared to 2.55 (1.48-4.41) mg/kg for buspirone. For each subject, the lowest dose that decreased responding by at least 50% was administered daily, immediately before the session, for up to 6 weeks. At the lowest daily dose of buspirone, complete recovery of baseline rates was observed in 3 pigeons. However, when the buspirone dose was increased, responding remained below control rates in all but one pigeon. During chronic midazolam administration, tolerance developed to the rate-decreasing effects of midazolam in 4 subjects. When saline was substituted for buspirone or midazolam, suppressed responding returned to predrug rates in all subjects. When the dose-response curves were redetermined, the postchronic ED50 for buspirone was 3.79 (2.10-6.82) mg/kg, which was not significantly different from the prechronic ED50, suggesting that tolerance did not develop to buspirone's rate-decreasing effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Salbutamol disposition and dynamics in conscious rabbits: influence of the route of administration and of the dose.

This study assessed the influence of dose and route of administration on salbutamol kinetics and hypokaliemic effect. Salbutamol plasma kinetics were studied in a first group of 6 rabbits who received 60, 800, and 60 micrograms/kg by the intravenous (iv), oral (po), and intratracheal (it) routes, respectively, at 1-week intervals. A second group of 6 rabbits received 120, 2400, and 120 micrograms/kg of salbutamol by the same three routes. Multiple blood samples were withdrawn to assay salbutamol and potassium. Following iv salbutamol (60 micrograms/kg), total plasma clearance was 82 +/- 5 ml/min per kg, apparent volume of distribution was 5.0 +/- 0.5 l/kg, and terminal half-life was 41 +/- 2 min. Similar values were estimated when 120 micrograms/kg of salbutamol was administered iv or was given po or it. The bioavailability of po and it salbutamol was approximately 1 and 20%, respectively. For the first group, the maximal decrease in plasma potassium elicited by salbutamol was 0.80 +/- 0.19, 0.48 +/- 0.22, and 0.78 +/- 0.46 mmol/l, and for the second group, maximal decrement was 1.31 +/- 0.37, 0.70 +/- 0.24, and 0.84 +/- 0.17 mmol/l for the iv, po, and it routes, respectively. Compared to salbutamol peak plasma concentrations, maximal decrease in plasma potassium appeared between 60 and 108 min later for the iv route, 90 and 25 min later for po and it routes, and for this reason, the hypokaliemic effect was not associated to salbutamol plasma concentrations. The hypokaliemic effect was dependent upon the route, e.g., po > it > iv.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary excretion of mercapturic acids and thiocyanate in rats exposed to acrylonitrile: influence of dose and route of administration

Adult male Sprague-Dawley rats were exposed acutely to acrylonitrile (ACN) according to 1 of 3 different routes of administration: inhalation (6 h), i.v., or i.p. Urinary metabolites measured 24 h after administration were 2-cyanoethylmercapturic acid (CMA), 2-hydroxyethylmercapturic acid (HMA) and thiocyanate (TCN). In all 3 series of experiments, the relationship between excretion of total urinary metabolites and the degree of exposure was reasonably linear. However, there was a marked influence of the route of administration on the pattern of metabolic excretion. For example, after i.p. and i.v. injection CMA was the most important metabolite while after inhalation it was TCN. Our results also indicate an important effect of the dose on the pattern of excretion for all types of administration.