Ch3o O Oh

Norcodeine

HO o OH

Normorphine

3.6.12.1. Metabolic pathway of heroin and morphine.

Approximately 5% of a dose of morphine is N-demethylated to normorphine. This metabolite is also pharmacologically active, although its relative potency is less than morphine and due to the low concentrations typically measured after morphine administration, may not contribute significantly to the overall pharmacological effects.

Metabolism occurs primarily in the liver with 90% of a dose excreted in the urine and 10% in the feces. There is extensive enterohepatic circulation of both conjugated and unconjugated morphine. Approximately 87% of a dose of morphine is excreted in the 72-h urine, 75% as morphine-3-glucuronide, 10% as free morphine, and the remainder as morphine-6-glucuronide, morphine-3-sulfate, normorphine, and conjugates. The clearance of morphine was found to vary between 1.2 to 1.9 L/min/70kg in several human studies.14

3.6.12.2 Heroin

Heroin, or 3,6-diacetylmorphine, was first synthesized from morphine by C.R. Wright in 1874. The Bayer Company of Germany subsequently marketed the drug as an analgesic in 1898. Currently in the U.S. heroin has no accepted medical use and is placed in Schedule I of the federal Controlled Substances Act of 1970.

Heroin is typically self-administered by intramuscular or intravenous injection and also by nasal insufflation ("snorting") or smoking. Peak heroin concentrations in blood are achieved within 1 to 5 min after intravenous and smoked administration17 and within 5 min after intranasal and intramuscular administration.18 In a study in which the method of smoked heroin delivery was optimized to reduce loses due to pyrolysis and sidestream smoke, Jenkins et al.17 reported similar pharmacokinetic profiles for the smoked and intravenous routes. Mean elimination half-lives for two subjects across three doses of heroin were 3.3 minnd 3.6 min, after smoked and intravenous administration, respectively. The mean residence time of heroin was less than 10 min after all doses by both routes. Cone et al.18 reported that the pharmaco-

kinetic profile of intranasal heroin was equivalent to that for the intramuscular route. Mean elimination half-lives (hours plus or minus SD) were determined to be 0.09 ± 0.05, 0.07 ± 0.02, and 0.13 ± 0.07, following intranasal administration of 6 mg and 12 mg, and intramuscular administration of 6 mg of heroin, respectively. The relative potency of intranasal heroin was estimated to be approximately one-half that of intramuscular administration.

It is known from in vitro studies that heroin is rapidly deacetylated to an active metabolite, 6-acetylmorphine, which is then hydrolyzed to morphine (Figure 3.6.12.1). Spontaneous hydrolysis to 6-acetylmorphine may occur under various conditions. Heroin is susceptible to base catalyzed hydrolysis but will also hydrolyze in the presence of protic compounds such as ethanol, methanol, and aqueous media.

The addition of two acetyl-ester groups to the morphine molecule produces a more lipophilic compound. Because heroin exhibits little affinity to opiate receptors in the mammalian brain, it has been postulated that it acts as a prodrug, to facilitate the entry of the active, but less lipophilic, compounds 6-acetylmorphine and morphine.

Following intravenous infusion of 70 mg of heroin to human volunteers, 45% of the dose was recovered in urine after 40 h. Over 38% was recovered as conjugated morphine, approximately 4% as free morphine, 1% as 6-acetylmorphine and 0.1% as heroin.12 Urinary elimination half-lives of 0.6, 4.4, and 7.9 hours were reported for 6-acetylmorphine, morphine, and conjugated morphine, respectively, after administration of 6 mg of heroin by the intramuscular route.19

3.6.12.3 Methadone

Methadone is a synthetic opioid, clinically available in the U.S. since 1947.12 It exists in the dextro- and levo-rotatory forms with the levo-isoform possessing approximately 8 to 50 times more pharmacological activity.20 Methadone acts on the central nervous and cardiovascular systems producing respiratory and circulatory depression. Methadone also produces miosis and increases the tone of smooth muscle in the lower gastrintestinal tract while decreasing the amplitude of contractions. It is used clinically for the treatment of severe pain and in maintenance programs for morphine and heroin addicts.12

Methadone is typically administered orally, with peak blood concentrations occurring after 4 h. Inturrisi and Verebely21 reported a peak plasma concentration of 75 ng/mL at 4 h after a single 15-mg oral dose. Concentrations declined slowly, with a half-life of 15 h, reaching 30 ng/mL by 24 h. A single 10-mg intravenous dose of methadone resulted in initial plasma concentrations of 500 ng/mL declining to 50 ng/mL after 1 to 2 h.22 Peak plasma concentrations (mean = 830 ng/mL) after 4 h were also observed with chronic oral administration of 100 to 200 mg/day.21 Concentrations of methadone reach a maximum in brain tissue approximately 1 to 2 h after an oral dose.20 Methadone is highly plasma protein bound (87%) with 70% bound to albumin.20 Methadone distributes rapidly to tissues, especially the lungs, liver, kidneys, and spleen. The volume of distribution is 4-5 L/kg.12

Methadone is metabolized in the liver by N-demethylation to produce unstable metabolites which undergo cyclization to form the metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP) (Figure 3.6.12.3). These metabolites and the parent drug undergo para-hydroxylation with subsequent conjugation with glucuronic acid. All three are excreted in the bile and are the major excretory products measured in the urine after methadone administration. Minor metabolites, methadol, and normethadol exhibit pharmacological activity similar to methadone but are produced in low concentrations.

Large individual variations in the urine excretion of methadone are observed depending on urine volume and pH, the dose and rate of metabolism. Acidifciation of the urine may increase the urinary output of methadone from 5 to 22%.20 Typically, following a 5-mg oral dose,

p-Hydroxylation and Glucuronide Conjugation

3.6.12.3. Metabolic pathway of methadone.

methadone and EDDP account for 5% of the dose in the 24-h urine. In those individuals on maintenance therapy, methadone may account for 5 to 50% of the dose in the 24-h urine and EDDP may account for 3 to 25% of the dose.

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