PHARMACOKINETICS OF SPECIFIC DRUGS

27

which may occur at high doses, may be due to dopamine release from dopaminergic neurons and also serotonin release from tryptaminergic neurons located in the mesolimbic area of the brain. Amphetamine and methamphetamine occur as structural isomers and stereoisomers. Structural isomers are compounds with the same empirical formula but a different atomic arrangement, e.g., methamphetamine and phentermine. Stereoisomers differ in the three-dimensional arrangement of the atoms attached to at least one asymmetric carbon and are nonsuperimposable mirror images. Therefore, amphetamine and methamphetamine occur as both D- and L-isomeric forms. The two isomers together form a racemic mixture. The D-amphetamine form has significant stimulant activity, and possesses approximately three to four times the central activity of the L-form. t is also important to note that the D- and L-enantiomers may have not only different pharmacological activity but also varying pharmaco!inetic characteristics. "hen indicated for therapeutic use, # to $% mg or # to &% mg of amphetamine or methamphet-amine, respectively, are administered orally. An oral dose of amphetamine typically results in a pea! plasma concentration of ''% ng(ml. & "hen abused, amphetamines may be self-administered by the oral, intravenous, or smo!ed route. The last route of administration is common for meth-amphetamine. "ith heavy use, addicts may ingest up to &%%% mg per day. 4.1.1 Absorption

Limited data are available on the ) absorption of amphetamine in humans. *ec!ett and +owland , reported serum concentrations of amphetamine in two healthy volunteers after a '#-mg oral dose of the D-isomer. -ea! serum concentrations of ./ and .% ng(ml were achieved at '.&# h when the volunteers0 urine was acidified. Slightly higher serum concentrations were observed 1#& and .2 ng(ml3 if the urine p4 conditions were not controlled. +owland . observed a pea! blood concentration of ,# ng(ml, & h after a '%-mg oral dose of D-amphetamine to a healthy $$-!g adult. The half-life for the D-isomer was '' to ', h compared with a ,56 longer half-life for the L-isomer. f the urine were acidified, excretion was enhanced and the half-lives of both isomers were reduced to approximately 2 h. # Amphetamine demonstrates a linear one-compartment open model over the dose range &% to &%% mg. 4.1.2 Distribution

The plasma protein binding of amphetamine in humans is approximately '$ to &%6 and is similar in drug-dependent and naive sub7ects.$ +esearch by +owland. and 8ran!sson and Anggard$ indicated that there was a difference in the volume of distribution between non-users 1,.# to ..$ L(!g3 and drug-dependent individuals 1$.' L(!g3. t has been suggested that the larger Vd observed in drug-dependent sub7ects may be due to a higher tissue affinity for amphetamine in these individuals. 9vidence to support this suggestion is found in studies with amphetamine-dependent animals in which higher tissue concentrations of amphetamine were found.2 4.1.3 Metabolism and Excretion

Amphetamine is metaboli:ed by deamination, oxidation, and hydroxylation. 8igure ..' illustrates the metabolic scheme for amphetamine. Deamination produces an inactive metabolite, phe-nylacetone, which is further oxidi:ed to ben:oic acid and then excreted in urine as hippuric acid and glucuronide con7ugates. n addition, amphetamine is also converted to norephedrine by oxidation and then this metabolite and the parent compound are p-hydroxylated. Several metabolites, including norephedrine, its hydroxy metabolite, and hydroxyamphetamine, are pharmacologically active. The excretion of amphetamine depends on urinary p4. n healthy men who were administered # mg of isotopically labeled D,L-amphetamine, approximately 5%6 of the dose was excreted