Relationship between brain levels of 3-(3-hydroxyphenyl)-N-n-propylpiperidine HCl enantiomers and effects on locomotor activity in rats.

After s.c. administration of 3-(3-hydroxyphenyl)-N-n-propylpiperidine HCl (3-PPP) to rats, plasma and brain levels were monitored in relation to the amount of spontaneous locomotor activity. Based on time-course relationships, concentration-effect curves were elaborated after administration of (-)3-PPP and (+)3-PPP in the dose range of 1 to 256 mumol.kg-1. Both enantiomers were readily absorbed and distributed, as evidenced by a close correlation between brain and plasma levels, brain levels being 7 to 9 times higher than those found in plasma. Plasma half-lives were 25 and 32 min for (-)3-PPP and (+)3-PPP, respectively. Plotting brain concentrations of (-)3-PPP against locomotor activity resulted in a good fit to a declining two-phase curve, in all probability reflecting preferential actions at pre- and postsynaptic dopamine receptors, respectively. These two underlying mechanisms could also be identified from the biphasic effects produced by (+)3-PPP on locomotor activity: suppression followed by stimulation, respectively. Together, these observations provide further support for the contention that at low doses, both enantiomers have sedative actions due to stimulation of inhibitory autoreceptors. With increasing doses, however, a postsynaptic receptor blockade will predominate for a partial agonist like (-)3-PPP, producing suppression of locomotion, whereas the full agonist, (+)3-PPP, will produce behavioral activation due to stimulation of postsynaptic receptors.

Single-dose kinetics of deuterium-labelled cannabinol in man after intravenous administration and smoking.

The single dose pharmacokinetics of deuterium-labelled cannabinol (2H2-CBN) were evaluated in six male cannabis users with different degree of abuse after smoking an average dose of 19 mg and after intravenous administration of 20 mg CBN. Plasma levels were measured for up to 72 h with selected ion monitoring by GC/MS using 2H7-CBN as internal standard. The systemic availability of smoked CBN was found to be 39 +/- 26% (min-max 6-65%). The mean plasma clearance was 19.1 +/- 2.6 ml min-1 kg-1 and the volume of distribution was determined to 50 +/- 23 l kg-1. The apparent terminal half lives for CBN were 32 +/- 17 h and 43 +/- 29 h after intravenous administration and smoking, respectively.

Pressor response of oral tyramine in healthy men given amiflamine and placebo.

During two baseline challenge tests, oral tyramine (50 to 400 mg) was given to 12 healthy men to find each individual's cardiovascular pressor response. All 12 subjects "tolerated" 200 mg oral tyramine, but three of the 12 developed an increment in systolic blood pressure greater than 30 mm Hg when given a dose of 400 mg. Thereafter, amiflamine, 5 mg bid (n = 8), or placebo, 1 capsule twice a day (n = 4), were given in a double-blind fashion for 7 days, and oral tyramine challenge tests (12.5 to 400 mg) were given on days 5 to 7. During dosing with amiflamine or placebo, no subject tolerated 400 mg oral tyramine and no difference between the two regimens was found with regard to tyramine response. Plasma concentrations of amiflamine and two of its metabolites were measured on days 4 to 7. Steady-state concentrations were reached within 4 to 5 days. Plasma concentrations of tyramine after 400 mg tyramine showed a positive correlation with the increase in systolic blood pressure (P less than 0.001).

Tolerance and pilot pharmacokinetics of amiflamine after increasing single oral doses in healthy subjects.

Oral doses of 1 to 100 mg amiflamine, a new reversible monoamine oxidase type A-selective inhibitor, were given for the first time in humans to six healthy men. No apparent pharmacologic effects were recorded until the 80 mg dose. After 100 mg, one subject developed symptoms indicative of an overdose. Amiflamine is extensively metabolized by two consecutive N-demethylations. The biotransformation patterns in plasma and urine were found to correlate with the debrisoquin metabolic ratio.

Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration.

The disposition of deuterium-labelled cannabidiol, 2H2-CBD, was studied in five young men who were marihuana smokers. The pattern of use ranged from infrequent to frequent use of the drug. Plasma concentrations, determined by mass fragmentography, were followed for 72 h after both intravenous administration of 20 mg 2H2-CBD and smoking of an estimated amount of 18.8-19.4 mg 2H2-CBD. Systemic availability after smoking was determined by comparing the areas under the plasma concentration versus time curves for the two treatments and was found to be 31 +/- 13%. A four-fold difference in the availability of the compound was noted for the five subjects. Based on the area under the curve and the dose after intravenous administration, a plasma clearance of 960-1560 ml min-1 was calculated. A terminal elimination phase was not reached at 72 h, but the kinetic parameters were estimated from the 72 h beta-elimination. A half-life of 31 +/- 4 h after smoking and 24 +/- 6 h after injection was estimated as well as a distribution volume of 2520 +/- 470 l (32.7 +/- 8.61 kg-1).

Correlations between in vitro dissolution rate and bioavailability of alaproclate tablets.

In two different absorption studies, quantitative correlations between the in vitro dissolution rate and the bioavailability have been shown after single administration of various tablet compositions of alaproclate hydrochloride to healthy subjects. Both statistical moment analysis and the use of empirical single value parameters were tested. For conventional tablets a linear relationship was obtained between mean dissolution time in vitro and in vivo. A similar relationship was obtained between the mean dissolution time in vitro and the mean residence time for controlled release tablets of the matrix type. It was also possible to establish an in vitro--in vivo correlation for these latter tablets by using the single point estimate of maximum plasma concentration as in vivo parameter. When comparing the mean dissolution time in vitro to the total area under the plasma drug concentration-time curve attained after different types of tablets, it is obvious that the extent of bioavailability of alaproclate will not fall below 80% of the value found for an aqueous solution until the mean dissolution time in vitro exceeds approximately 3 hr. Statistical moment analysis seems to have a broader applicability than the use of empirical point estimates, and it seems to be useful both for conventionally dissolving tablets and controlled release tablets.

Guide to the analysis of phencyclidine and its metabolites in biological material.

Phencyclidine was introduced as an anaesthetic in 1960; and has now become a major drug of abuse in some countries. The rapid advance in the various fields of analytical chemistry during the past decades has made it possible to measure the levels of the compounds in tissues and body fluids. These methods may also be used to study the metabolism and pharmacokinetics of PCP. The resulting publication is an updated guide to these analyses particularly with the application of these techniques in human intoxication.

Quantification of delta 1-tetrahydrocannabinol in tissues and body fluids.

The search for the psychoactive constituents of the plant Cannabis sativa L has revealed over 420 compounds to date. The synthesis of delta 1-tetrahydrocannabinol finally established the main active component of cannabis. THC is a potent drug, and plasma levels (except initially) are of the order of a few nanograms per milliliter. During the last few years, various methods based on mass spectrometry, RIA etc. have made it possible to quantitate non labelled THC and metabolites in plasma. These plasma level determinations of THC may be important for correct clinical diagnosis of cannabis intoxication, and for drug interaction studies. The various analytical techniques for cannabinoids are discussed, and updated in this paper.

Identification of in vitro metabolites of delta 1-tetrahydrocannabinol formed by human livers.

Metabolism of delta 1-tetrahydrocannabinol (delta 1-THC) in humans, has been studied in vitro with the 10,000g supernatant fraction of three human livers. One of the livers (H-13) showed very high enzyme activity compared to the other two. The metabolites were characterized by their mass spectra and in most cases by comparison of their mass spectra and chromatographic properties with those of available synthetic references. The metabolic pattern was similar in all three livers, with 7-hydroxy-delta 1-THC as the most abundant metabolite. Furthermore, they all formed compounds oxygenated in the 6-position. Sidechain oxygenation was most pronounced with H-13, whereas trace mounts of 7-hydroxy-epoxide were formed by livers H-13 and H-15.

Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users.

Deuterium labelled delta 1-tetrahydrocannabinol was administered intravenously (5.0 mg) and by smoking (10.0 mg) to five heavy and four light marihuana users. All subjects smoked an estimated amount of 8.6-9.9 mg delta 1-tetrahydrocannabinol. The plasma levels of delta 1-tetrahydrocannabinol were followed for 48 hours and in two subjects fof 72 hours after administration. The systemic availability after inhalation calculated from the area under curve values was in the range of 27 +/- 10% for the heavy users and 14 +/- 1% for the light users. There was little difference between the groups with regard to the amount of smoked delta 1-tetrahydrocannabinol or plasma levels and area under curve values obtained after i.v. administration. Thus, it seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users. It is also indicated that heavy users prefer slightly higher delta 1-tetrahydrocannabinol plasma levels than light users. Based on the area under curve values after i.v. administration, a plasma clearance of 760-1190 ml min-1 was calculated. The elimination half-life of delta 1-tetrahydrocannabinol is more than 20 hours. The present results do not suggest that tolerance or sensitivity to delta 1-tetrahydrocannabinol in heavy users is readily achieved.

Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication?

Plasma concentrations of THC were measured by gas-liquid chromatography and mass spectrometry following three routes of administration and correlated with clinical effects. Plasma concentrations peaked at 3 minutes after intravenous injection and then sharply declined. The peak "high" occurred at 30 minutes while plasma concentrations were declining. This lag between plasma concentration and "high" continued during most of the span of the drug's effects. The situation was quite similar following smoking, except that peak plasma concentrations were lower. After oral administration of THC, absorption was slow, with peak concentration occurring at 1 to 2 hours. Plasma concentrations were much lower. Correlations between plasma concentrations of drug and "high" were significant but not impressive. The degree of "high" was quite variable in relation to the prevailing plasma concentration. Conjunctival injection was found so long as plasma concentration of THC could be measured. Pulse rate increases occurred at lower concentration after oral administration than after the other two routes. It is unlikely that a range of plasma concentrations can be reliably equated with impaired performance. The mode of administration will become important should THC or some homolog become a therapeutic agent.

Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis.

delta 9-Tetrahydrocannabinol (delta 9-THC) was administered in a crossover design by smoking and IV injection to groups of heavy and light users of marihuana. Plasma concentrations of delta 9-THC were similar for the groups after IV injection of 5.0 mg delta 9-THC, but the AUC0-240 min showed a trend towards lower values for the heavy user group. To achieve a maximum desired "high", both groups smoked similar amounts (about 13 mg) of delta 9-THC. Heavy users tended to have higher plasma levels than light users. The systemic availability of smoked delta 9-THC was significantly higher for the heavy users (heavy users 23 +/- 16% vs 10 +/- 7% for light users). These results also indicate that heavy cannabis users smoke more efficiently than casual smokers. Both light and heavy users showed more clinical effect following IV administration than after smoking. The response of the heavy users, both with respect to effect on heart and "high", was quite comparable to that of light users. The present study does not suggest that tolerance readily develops in heavy users.

Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking.

Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.

Chemical synthesis and biological occurrence of carboxylic acid metabolites of delta1(6)-tetrahydrocannabinol.

Potential metabolites of (-)-3,4-trans-tetrahydrocannabinol (THC) with a carboxylic acid function in the side chain were synthesized as their methyl esters in the delta1(6)-series. The chromatographic and mass-spectrometric properties of the five side-chain homologues were examined and utilized to facilitate the isolation and the identification of the corresponding monocarboxylic acid metabolites of delta1(6)-THC in the mouse, guinea pig, and rabbit formed after ip administration. The metabolites were identified by gas chromatography and mass fragmentography. In mouse liver delta1(6)-THC-7-oic acid and 3'',4'',5''-trisnor delta1(6)-THC-2''-oic acid were identified as metabolites. In guinea pig liver these acids occurred together with 4'',5''-bisnor-delta1(6)-THC-3''-oic acid and 5''-nor-delta1(6)-THC-4''-oic acid. Rabbit liver contained delta1(6)-THC-7-oic acid, 2'',3'',4'',5''-tetranor-delta1(6)-THC-1''-oic acid and 4'',5''-bisnor-delta1(6)-THC-3''-oic acid. Further, the structure of three dicarboxylic acid metabolites of delta1(6)-THC in rabbit kidney were determined by mass spectrometry and proton magnetic resonance spectroscopy.

Acidic metabolites of delta1-tetrahydrocannabinol isolated from rabbit urine.

The in vivo metabolism of delta1-tetrahydrocannabinol (delta1-THC) was investigated in the rabbit after i.v. administration. Thirteen acidic metabolites were isolated from rabbit urine and identified by gas chromatography-mass spectrometry and by proton magnetic resonance spectroscopy. One additional metabolite was tentatively identified. All but three were new metabolites and all but one were oxidized in the pentyl side chain. The metabolites included dicarboxylic acids, monocarboxylic acids and mono- or dihydroxylated derivatives thereof. However, the dicarboxylic acid metabolites were the most prominent.

Cocaine in blood of coca chewers.

Coca leaves (Erythroxylum coca Lamarck) and powder (5 - 10 g) were taken orally by human subjects in the same way as South American natives do. The cocaine, as measured by mass fragmentography, was immediately detected in the blood, reached peak concentrations from 10 - 150 ng/ml plasma at 0.38 - 1.95 hours, and persisted in the plasma for more than 7 hours. Half-lives of the elimination of cocaine were calculated and ranged from 1.0 to 1.9 hours. The absorption half-lives ranged from 0.2 to 0.6 hours. The shape of the curves fits with the subjective effects reported. There is no reason to believe that the stimulating effect achieved by the use of either coca leaves or powder is not due to cocaine.