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3/17/2015 Prodrugs are Drug Precursors – Metabolized to Active Drugs In Vivo Prodrug Active drug psilocybin psilocin heroin morphine Vyvanse® amphetamine Prodrugs are Drug Precursors – Metabolized to Active Drugs In Vivo Prodrug Active drug psilocybin psilocin heroin morphine Vyvanse® amphetamine 1 3/17/2015 Why Prodrugs? • Prodrugs may have better solubility, permeability, bioavailability, or can better access target Heroin crosses BBB more readily than morphine • Prodrugs may be a “slow‐release” formulation ‐ improved half‐life Vivance® is once‐daily dosing versus Adderall® • Some prodrugs are natural products (e.g. psilocybin) Psilocybin Metabolism psilocybin prodrug psilocin active drug phosphatase inactive metabolites monoamine oxidase glucuronosyl transferase 2 3/17/2015 Many Psychedelic Drugs Act Through Agonizing Serotonin Receptors – Primarily 5‐HT2A O N serotonin 5‐hydroxytryptamine (5‐HT) N H N H psilocin LSD Multiple 5‐HT receptor subtypes N N H DMT Amphetamine in ADHD Pharmacotherapy Adderall® Adderall XR® Adderall XR Mixed amphetamine salts (dextro and levo) 6‐8 h duration 10 h duration 10 h duration Dexedrine® Dextrostat® Single isomer amphetamine (dextro) 6‐8 h duration Vyvanse® Amphetamine pro‐drug (lysine bound) 10 h duration active isomer (dextro) less active isomer (levo) Amphetamines used chronically in treatment of ADHD do not display neurotoxicity as does methamphetamine 3 3/17/2015 Vyvanse® ‐ Amphetamine Prodrug in vivo Vyvanse® prodrug dextro amphetamine lysine (amino acid) Slow release of amphetamine Less potential for abuse via crushing and snorting or injecting Synthesis of Diacetylmorphine (Diamorphine, Heroin) Nucleophilic alcohols react with electrophilic reagent acetic anhydride Alcohols in morphine converted to esters in heroin – is heroin more or less hydrophobic? 4 3/17/2015 Heroin Metabolism HO O O H N O heroin morphine 6‐monoacetylheroin detection in urine distinguishes between heroin and other opioid use Heroin is a pro‐drug for morphine with 2‐4 x greater potency Heroin crosses BBB more readily (hydrolysis can occur in brain or periphery) Undergoes extensive first‐pass metabolism when taken orally – hence, injected or snorted Opioid Drug Testing – Differentiating Heroin From Codeine and/or Morphine heroin 6‐monoacetylheroin morphine Detection of 6‐monoacetyl heroin and its downstream metabolites indicates heroin use codeine 5 3/17/2015 Opioid Drug Testing – False Positives Due to Poppy Seed Consumption 1 g poppy seeds contains up to 33 mcg morphine, 14 mcg codeine Positive drug tests can result from moderate consumption (e g 2 poppy seed rolls 1 5 g) Positive drug tests can result from moderate consumption (e.g. 2 poppy seed rolls, 1.5 g) Standard cutoff now increased to 2 mcg / mL GC‐MS verification to distinguish between legal consumption and illicit drug use: • Examine morphine : codeine ratio • Look for presence of 6‐monoacetylmorpine, a heroin metabolite p y p 6
