Ronald B. Pontani

Effect of caffeine on cocaine locomotor stimulant activity in rats

The effect of caffeine on the locomotor stimulant activity induced by intravenous cocaine in rats was investigated. Low doses of caffeine (20 mg/kg IP) potentiated the locomotor activity induced by 1, 2.5 mg/kg intravenous doses of cocaine and higher doses of caffeine (50, 100 mg/kg IP) had no significant effect. The locomotor stimulant effect of 20 mg/kg IP dose of caffeine per se in vehicle was significantly higher and that with 100 mg/kg dose significantly lower than that of the vehicle control. Thus caffeine produced dose-dependent effects on cocaine-induced locomotor stimulant activity, with low dose potentiating and higher doses having no significant effect on such activity. Pharmacokinetic or dispositional factors did not appear to play a role in potentiation of cocaine locomotor stimulant activity by caffeine.

Stereospecific potentiation of opiate analgesia by cocaine: predominant role of noradrenaline

&NA; Cocaine hydrochloride (50 mg) pellets implanted subcutaneously in male Wistar rats potentiated the analgesia of morphine, levorphanol, methadone and buprenorphine as measured by the tail‐withdrawal test. Potentiated opiate analgesia was abolished by naloxone and further enhanced by desipramine and phenoxybenzamine. Yohimbine, &agr;‐methyl p‐tyrosine, haioperidol, zimelidine, methysergide, p‐chlorophenylalanine produced no significant effect on potentiated opiate analgesia. Pseudococaine (dextro‐cocaine), which is several‐fold less potent than cocaine as an inhibitor of noradrenaline and dopamine reuptake in the CNS, had no significant effect on opiate analgesia. Analgesia produced by low doses of baclofen, a GABA agonist, was also not potentiated by cocaine. This study suggests a predominant role for noradrenaline in the Stereospecific potentiation of opiate analgesia by cocaine.

Disposition in the rat of buprenorphine administered parenterally and as a subcutaneous implant

Disposition of [15, 16(n)-3H]buprenorphine in the rat has been investigated after a single 0.2 mg/kg i.v. bolus dose and continuous administration via a s.c. implantable long-acting delivery system. After the i.v. injection, the tri-exponential decay of drug from brain occurred with t1/2 values of 0.6, 2.3 and 7.2 h, respectively (plasma t1/2 0.5, 1.4 h, third phase not estimated due to sustained concn.) Decay of drug from another high-affinity binding site in brain occurred with t1/2 values of 1.1 and 68.7 h, respectively. Fat and lung had higher concn. than other tissues and plasma. No metabolites of drug were detected in brain. Unmetabolized drug excreted in urine and faeces one week after i.v. injection were 1.9 and 22.4% of dose, respectively, and 92% of the dose was accounted for in one week. Urinary metabolites (%) were: conjugated buprenorphine 0.9; norbuprenorphine (free 9.4, conjugated 5.2); tentative 6-O-desmethylnorbuprenorphine (free 5.4, conjugated 15.9). Peak plasma concn. of buprenorphine occurred four weeks after s.c. implantation of a long-acting 10 mg 3H-buprenorphine pellet, and apparent dissociation half-lives of drug from low- and high-affinity binding sites in brain were 4.6 and 6.8 weeks, respectively. Fat, spleen and skeletal muscle had higher concn. than other tissues and plasma. No significant difference in brain morphine concn. was observed in placebo and nonlabelled buprenorphine-pelleted animals after a 2 mg/kg i.v. challenge dose of 3H-morphine. This study emphasizes the importance of high-affinity binding of buprenorphine in brain and subsequent slow dissociation as a prime factor in its prolonged agonist/antagonist effects and higher potency than other narcotic agonists.

Pharmacokinetics and Metabolism of [3H] Thebaine

1. A method is described for determination of [3H]thebaine in biological materials with sensitivity of 10–20 ng.2. Following a 5 mg/kg subcutaneous dose of [3H]thebaine to rats, max. brain and plasma concns. were 937 ng/g and 1076 ng/ml at 0.5 and 1 h, respectively; these declined to non-detectable levels at 24 h. The corresponding half-lives of thebaine in rat plasma and brain were 1.1 and 1.5 h, respectively.3. Free thebaine excreted in 96 h urine and faeces following a 5 mg/kg subcutaneous dose was 16.7 and 4.3% and total radioactivity was 43.4 and 8.4%, respectively.4. Extensive metabolism of thebaine occured in rat; several metabolites were identified by chromatography, and metabolites were also shown to be present in the brain.5. Rat plasma proteins and human albumin bound thebaine (1–100 µg/ml) to the extent of 66.7 and 27.3%, respectively; binding to plasma proteins was independent of thebaine concentration.6. Rapid metabolism and elimination of thebaine prevents its persistance in brain. These fi...

Disposition of [3H] phencyclidine in the rat after single and multiple doses

After a 2.5 mg/kg i.v. bolus injection of [3H] PCP to male Wistar rats, the half-lives (α and β phases) in plasma were 0.25 and 2.0 hr respectively. PCP was barely detectable in plasma 16 hr after inj. Decay of PCP from brain provided half-lives of 0.25, 3.3, 101 hr respectively. The brain to plasma and adipose tissue to plasma conc. ratios of PCP ranged between 7 to 15 and 31 to 100 respectively. The excretion of PCP (% dose) in urine and feces was 4,0.7 and with 25 mg/kg i.p. injection 2.7, 1.5 respectively; cumulative excretion with these 2 doses 71, 42 respectively. Oxidative hydroxylation in all 3 rings, conjugation, N-dealkylation, N-oxidation, dihydroxylation were the metabolic pathways of PCP. PCP and metabolites persisted for prolonged periods in adipose tissue and brain. On multiple dosing of PCP (25 mg/kg i.p.), brain and plasma levels were significantly lower in chronic as compared to the acute group. Concurrently higher values of metabolites and higher ratios of total metabolites to free drug conc. in plasma occurred in chronic as compared to the acute group. Data suggest that chronic treatment of rats with PCP enhanves its metabolism by induction of hepatic microsomal enzymes.

Intravenous kinetics and metabolism of [15,16-3H]naltrexonium methiodide in the rat.

After a 4 mg kg−1 bolus intravenous dose of [15,16‐3H]naltrexonium methiodide to the rat, brain to plasma concentration ratios of the compound were 0.031 to 0.228 between 0.25 to 6 h after injection and the t½β; in plasma and brain were 2.92 and 7.61 h, respectively. Ethyl acetate‐extracted radioactivity due to metabolites in plasma decayed with t½β; 1.83 h and the ratios of plasma concentration of metabolites to quaternary compound between 0.25 and 6 h were 0.014–0.026. Only unconjugated 7,8‐dihydro‐14‐hydroxynormorphine, naltrexone and traces of 7,8‐dihydro‐14‐hydroxynormorphinone were the metabolites in plasma. Naltrexone (but not normetabolites) was present only in traces in brain up to 0.5 h after injection and not at later times.

A long-acting buprenorphine delivery system

A subcutaneously implantable buprenorphine delivery system utilizing cholesterol-glyceryltristearate matrix for prolonged release of drug is described. Implantable cylindrical pellets of buprenorphine (cholesterol 36 mg, glyceryltristearate 4 mg, buprenorphine hydrochloride 10 mg), diameter 3 mm, length 6 mm blocked the antinociceptive action (hot plate, 55 degrees C) of 10 mg kg-1 SC challenge dose of morphine in rats for 12 weeks or more (longer periods not evaluated). The cumulative percent release of buprenorphine from the test devices 2, 4, 6, 10 and 12 weeks after implantation was 27.4, 35.9, 37.6, 39.9 and 43.1, respectively. The release of buprenorphine from 10 mg pellets approximated first-order kinetics with half-lives of 0.85 and 50.24 weeks, for alpha and beta phases, respectively. The test devices possess the desirable characteristics of simplicity, biocompatibility, nontoxicity, ease of sterilization with ethylene oxide, small size for ease of insertion and removal, minimal encapsulation by surrounding tissue and an extended period of drug release unaffected by body metabolism. No side effects were seen in implanted rats which fed well and gained weight during entire treatment. Neither deterioration of implant nor any gross anatomic changes at implant site were apparent 12 weeks after pellet implantation.

Evidence for a new metabolite of morphine-N-methyl-14C in the rat.

Abstract Evidence has been presented for the formation in vivo in the rat of a new urinary metabolite of morphine, to which 2,3-dihydrodiol structure has been tentatively assigned. In vitro, rat brain and liver homogenates were shown to produce a 2,3-catechol type of metabolite by aromatic hydroxylation of morphine. Small amounts of morphine N-oxide and normorphine were also identified as metabolites in vitro by liver homogenates. Sequential oxidation of morphine by alkaline ferricyanide and hydrogen peroxide and Cu2+ has been shown to produce a zwitterionic 2,3-quinone, whose Chromatographic properties appeared similar to those of the hydroxylated metabolite formed in vitro by rat brain and liver homogenates.

Metabolism of norcocaine, N-hydroxy norcocaine and cocaine-N-oxide in the rat

1. The metabolism of [3H]norcocaine, N-hydroxy[3H]norcocaine and cocaine-N-oxide has been investigated in rats after i.v. injection. 2. The biological t 1/2 of norcocaine (dose 2 mg/kg i.v.) in plasma, liver and brain were 0.4, 1.6, 0.5 h, respectively and the compound was not detectable in the central nervous system 6 h after injection. The % dose of norcocaine excreted unchanged in urine and faeces in 96 h were 0.7 and 1.0, respectively. Benzoylnorecgonine, norecgonine, norecgonine methyl ester and an unidentified compound were excreted in urine. 3. The biological t 1/2 of N-hydroxynorcocaine (5 mg/kg i.v.) in brain and plasma were 0.3, 1.6 h respectively and only 1.3 and 1.6% of dose were excreted unchanged in urine and faeces in 96 h. N-Hydroxybenzoylnorecgonine and N-hydroxynorecgonine methyl ester were the major urinary metabolites. N-hydroxynorcocaine was not metabolized to norcocaine in vitro by liver microsomes. Doses of greater than 7.5 mg/kg i.v. resulted in death of rats by cardiorespiratory arrest. 4. Cocaine-N-oxide (50 mg/kg i.v.) yielded ecgonine-N-oxide methyl ester as its major metabolite; other minor metabolites were cocaine (0.5%), norcocaine (1%), benzoylecgonine, ecgonine, ecgonine-N-oxide, along with minor amounts of unmetabolized compound. Lethality of cocaine-N-oxide (100 mg/kg i.v.) was possibly due to metabolism to norcocaine and cocaine.

Increased brain uptake of morphine in the presence of the antihistamine tripelennamine

Disposition of [6 3H (N)]morphine in plasma, brain and liver of rats was studied 15 min after intravenous injection of either a 2 mg kg−1 dose of morphine or a combination of the same dose of morphine with a 6 mg kg−1 dose of tripelennamine. The concentrations of morphine in brain and the brain to plasma morphine ratios in animals receiving the combination of drugs concurrently were significantly higher than those in the control morphine group. No significant differences were seen in the morphine or morphine metabolite concentrations in plasma and liver or liver to plasma morphine concentration ratios in the 2 groups. Data suggest that pharmacokinetic factors play a role in the potentiation of opiate effects by antihistamine on concurrent i.v. administration of the two drugs.