Chyan E. Lau

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics

Abstract  Rationale: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. Objectives: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. Methods: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (Fsrr and Frr). Results: IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of Fsrr (13.67%) and Frr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. Conclusions: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine.

Pharmacokinetics and bioavailability of midazolam after intravenous, subcutaneous, intraperitoneal and oral administration under a chronic food-limited regimen : relating DRL performance to pharmacokinetics

The effects of midazolam on animal behavior often are evaluated under a chronically food-limited regimen, which is used to implement food-reinforced performance, but the corresponding pharmacokinetics are lacking. The present study investigated the pharmacokinetics of midazolam after IV, SC, IP, and PO administration in food-limited rats. A two-compartment model best described the concentration-time profiles for the four routes of administration. The rate of midazolam absorption was rapid, and peak concentrations were attained in less than 7 min for the three extravascular routes. The mean volume of distribution of the central compartment and clearance were 0.77 l/kg and 2.03 l/h per kg, respectively. Midazolam elimination half-lives for the four routes of administration ranged from 23.1 to 49.5 min, and metabolites could not be detected. The mean absolute bioavailability was route-dependent: 39.3% (SC) 19.2% (IP) and 4.6% (PO). The markedly low oral bioavailability found in food-limited rats contrasted to the value reported for free-feeding rats (45%). Although the IP route yielded the highest maximum concentration on occasion, serum midazolam concentration-time profiles were variable, but did correspond to respective sedative responses. DRL 45-s performance after SC, IP, and PO administration further supported the advisability of using the SC route of administration, as opposed to the IP route, for studying midazolam dose-response relations. The bioavailability values assessed from DRL performance also agree with the measured pharmacokinetic values.

Caffeine has similar pharmacokinetics and behavioral effects via the IP and PO routes of administration

Caffeine administered intraperitoneally (i.p.) or orally (p.o.) decreased the reinforcement rate and increased the nonreinforced response rate in a dose-related fashion under a differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions. These effects were similar following both routes of caffeine administration. The parallel pharmacokinetics for i.p. and p.o. caffeine were each determined and related to the respective effects of caffeine on reinforcement rate. Serum caffeine concentrations were similar across the session after the absorption phase for a given dose. Consequently, the effect remained in approximately the same range within a dose, and no single dose possessed a full concentration-effect relation for the two routes. The effects of i.p. and p.o. caffeine on reinforcement rate plateaued at doses higher than 40 mg/kg, which produced a serum caffeine concentration of approximately 25 microg/ml regardless of the route of administration. The EC50 values were 7.34 and 9.93 microg/ml for i.p. and p.o. caffeine, respectively. This study as well as our previous studies demonstrated that the i.p. route is dependable for studying caffeine dose response relations but not for studying other drugs (e.g., midazolam). The possible mechanism accounting for this difference is discussed.

Tolerance to oral and IP caffeine: Locomotor activity and pharmacokinetics

Locomotor activity increase was a bitonic function of acute caffeine IP doses (2.5-40 mg/kg) in rats. When the schedule-induced polydipsic, orally self-administered dose of caffeine was increased over blocks of daily 3 h sessions from 9.3 to 36.5 mg/kg, postsession activity increased monotonically as a function of dose. The rate of tolerance development to the increase in locomotor activity produced by caffeine depended on the route of administration. Tolerance onset occurred on the fourth day of chronic IP doses, but remained incomplete after 21 doses. With the highest dose level of oral caffeine self-administration, tolerance developed on day 13, but remained incomplete even after 17 doses. Acute tolerance occurred for each of the IP doses, whereas a linear relation between locomotor activity and serum caffeine concentration was obtained after oral self-administration. There were two- to threefold higher locomotor activity AUCs(4 h) with oral caffeine at three dose levels compared to the activity AUCs(4 h) for IP doses.

Simultaneous determination of flurazepam and five metabolites in serum by high-performance liquid chromatography and its application to pharmacokinetic studies in rats.

A reversed-phase high-performance liquid chromatographic method is described which allows the quantification of flurazepam and five of its metabolites with a single, isocratic determination. In addition, it has the advantage of possessing a low detection limit and high precision. A 2 mm I.D. column was used to minimize sample size (50 microliter), increase sensitivity and reduce solvent consumption. The method was used to demonstrate that N-1-desalkylflurazepam, the major metabolite, has a short half-life in the rat in contrast to its prolonged life in humans.

Dose-dependent surmountability of locomotor activity in caffeine tolerance

For two chronic intraperitoneal caffeine dose regimens (10 and 80 mg/kg per day), tolerance developed rapidly (2-3 days) to the stimulatory effects of caffeine on locomotor activity. However, surmountability of the tolerant activity rate levels by caffeine administration was dose dependent: Activity rate was restored fully by acute caffeine administration for the 10 mg/kg per day series, but not for the 80 mg/kg per day series. The extent of tolerance was also dose-dependent: Tolerance was incomplete for the low-dose daily caffeine series but complete for the high-dose series. Upon discontinuation of daily caffeine dosing, activity rate decreased to the original baseline levels for both chronic series. Caffeine tolerance and the quantification of its surmountability may be explained by the pharmacokinetics of caffeine and the upregulation of adenosine receptors.

Orally self-administered cocaine: Reinforcing efficacy by the place preference method

In three separate place preference conditioning (PPC) experiments, groups of rats were exposed to different modes of receiving cocaine: IP cocaine doses (7.5 mg/kg), PO cocaine self-administered bolus doses (15 mg/kg), and 1-h schedule-induced cocaine-solution drinking sessions (19.1 mg/kg). Oral cocaine self-administration of PO bolus and schedule induction took place in situations that preceded transfer into an apparatus for PPC sessions. Thus, the reinforcing efficacies of the pharmacological consequences of both oral cocaine self-administration methods were evaluated by a procedure separate from the self-administration behavior itself. The IP cocaine dose imposition and the two oral cocaine self-administration arrangements all resulted in dose-exposure conditions sufficient for the production of PPC. The serum and brain cocaine pharmacokinetics sufficient for the production of reinforcing efficacy were measured and related to previous data.

Schedule-induced cocaine drinking: Choice between cocaine and vehicle

Rats were exposed to daily 3-hr schedule-induced polydipsia sessions (fixed-time 1-min food-pellet delivery) with two drinking fluids available: cocaine solution and water. Fluid position was alternated daily. Polydipsia occurred mostly from a preferred-side spout (position preference) until cocaine solution concentration was increased to between 0.52 and 1.04 mg/ml and animals drank mostly water. Within a lower concentration range (0.28-0.6 mg/ml) maximum session cocaine intakes ranged from 54.3 to 120.1 mg/kg. Postsession serum cocaine levels were about 200 ng/ml. At individually chosen cocaine solution concentrations, the addition of saccharin to the solution did not increase cocaine intake, but a compound solution (saccharin plus glucose) did. With progressive dilution of the compound vehicle, an almost complete preference for cocaine solution was maintained. But with a return to water as the vehicle, animals reverted to a position preference after a few sessions, although one maintained a clear cocaine preference. Schedule-induced polydipsia produced chronic, oral self-administration of cocaine resulting in pharmacologically significant intakes and serum levels.

Simultaneous determination of cocaine and its metabolites with caffeine in rat serum microsamples by high-performance liquid chromatography

A single, isocratic high-performance liquid chromatographic method is described for the determination of cocaine and three of its metabolites along with caffeine in serum microsamples (50 microliters). The small sample size permits the tracking of pharmacokinetic data over time in individual, small animals. The method also was used to demonstrate that cocaine, benzoylecgonine and norcocaine in rat serum samples were stable for at least a month without the presence of sodium fluoride.

Intravenous and oral clozapine pharmacokinetics, pharmacodynamics, and concentration-effect relations: acute tolerance.

We examined the pharmacokinetics and pharmacodynamics of intravenous (1-5 mg/kg) and oral clozapine (2.5-10 mg/kg) in rats (terminal half-life=81.8 min; oral bioavailability=5.32%). Both dose- and concentration-effect relations of clozapine were characterized. Clozapines effects were similar to those of benzodiazepines because of the similarity in effect-time profiles between the two classes of drugs. The IC(50) value increased as a function of dose; consequently, clozapines relative potency decreased linearly with the logarithm of AUC((0-infinity)), or bioavailable dose regardless of route of administration. The IC(50) is an index for the sensitivity of behavioral performance to clozapine; relative potency provides an index for estimating the extent of acute tolerance. As IC(50) increases, relative potency decreases, and consequently, acute tolerance increases. Our results demonstrated that greater acute tolerance was observed for i.v. clozapine than for p.o. clozapine; however, clozapine exhibited a single concentration-effect relation across dose and route of administration after correcting for relative potencies.