Pharmacokinetics of methamphetamine self-administered to human subjects by smoking S-(+)-methamphetamine hydrochloride.

S-(+)-methamphetamine hydrochloride ("ice") is abused by smoking (inhaling the vapors of the material). Male human volunteers inhaled the drug from a pipe heated at 300 degrees-305 degrees C for an average inhaled dose of 21.8 +/- 0.3 (SE) mg. The same volunteers were given an intravenous injection of 15.5 mg of S-(+)-methamphetamine hydrochloride. Methamphetamine and its metabolite amphetamine were analyzed in plasma, saliva, and urine by gas chromatography. The bioavailability of smoked methamphetamine was 90.3 +/- 10.4%. (Oral bioavailability calculated from this study and a previous one was 67.2 +/- 3.1%). The geometric mean plasma half-life was 11.1 hr for smoked methamphetamine and 12.2 hr for the intravenous drug. These values agreed with urinary excretion rate data. The volume of distribution in the elimination phase was 3.24 +/- 0.36 liter/kg for the smoked dose and 3.73 +/- 0.59 liter/kg for the intravenous dose. The mean residence times were 11.5 +/- 0.5 hr and 11.3 +/- 1.74 hr for the two routes. Metabolic clearance represented 58 and 55%, respectively, of the total clearance. Significant amounts of the drug (37-45% of the nominal dose) were excreted in urine as methamphetamine and lesser amounts (7% of the nominal molar dose) as amphetamine. Renal clearance was equivalent for the two routes. Methamphetamine concentrations in plasma after inhalation showed a plateau. A model involving both a fast and a slow input function fit the data from 4 of the 6 subjects and indicated a terminal elimination rate that agreed with results from model-independent pharmacokinetic calculations. The drug caused significant subjective and cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans.

The pharmacokinetics of orally administered S-(+)-methamphetamine-d3 were investigated in human male volunteers before and after a 13-day course of a slow release form of S-methamphetamine hydrochloride. A one-compartment pharmacokinetic model incorporating a lag time fits the data best. The average elimination half-life was 10.1 hr (range of 6.4-15.1 hr). There were no statistically significant differences in pharmacokinetic parameters when a low dose (0.125 mg/kg) was given before and after the 13-day oral regimen. When a higher challenge dose (0.250 mg/kg) was used, the maximum plasma concentration of methamphetamine-d3 was slightly but significantly greater when the test dose was given at the end of the oral dosing period than when it was given at the beginning. Although minor differences in pharmacokinetics occur after subchronic treatment with low doses of methamphetamine, their result would be to increase plasma concentration of the drug. Therefore, development of pharmacodynamic tolerance to methamphetamine could not be explained on the grounds of a change in pharmacokinetics.