Drug Metabolism: Phase I and Phase II Metabolism

• Introduction:

  • Lipophilic drug properties that promote passage through biological membranes and facilitate reaching site to drug action inhibit drug excretion.

    • Note: renal excretion of unchanged drug contributes only slightly to elimination, since the unchanged, lipophilic drug is easily reabsorbed through renal tubular membranes.

  • Biotransformation of drugs to more hydrophilic molecules is required for elimination from the body

    • Biotransformation reactions produces more polar, hydrophilic, biologically inactive molecules -- that are more readily excreted.

      • Sometimes metabolites retain biological activity and may be toxic.

    • Drug biotransformation mechanisms are described as either phase I or phase II reaction types.

• Phase I and Phase II Reactions Overview

  • Phase I characteristics

    •  Parent drug is altered by introducing or exposing a functional group (-OH,-NH₂, -SH)

    •  Drugs transformed by phase I reactions usually lose pharmacological activity

    •  Inactive, prodrugs are converted by phase I reactions to biologically-active metabolites

    •  Phase I reaction products may:

      • Be directly excreted in the urine

      • React with endogenous compounds to form water soluble conjugates.

• Phase II characteristics

  • Parent drug participates in conjugation reactions that form covalent linkage between a parent compound functional group and

    • • Glucuronic acid

      • Sulfate

      • Glutathione

      • Amino acids

      • Acetate

  • Conjugates are highly polar, and generally biologically inactive. 

    • One exception to this rule is a morphine metabolite, morphine glucuronide which is a more potent analgesic compared to the parent compound. 

    • Conjugates tend to be rapidly excreted in the urine.

    • High molecular weight conjugates  are more likely excreted in the bile.

      • The conjugate bond may be cleaved by intestinal flora with the parent compound released back to the systemic circulation. 

        • This process, "enterohepatic recirculation" results in delayed parent drug elimination and a prolongation of drug effects.