• Absorption

  • Fick's Law

• Routes of Administration

• First-Pass Effect

• Pulmonary Effects

• Pharmacokinetics

  • Volume of distribution

  • Clearance

    • Renal clearance: clearance of unchanged drug and metabolites

      • Other Factors Affecting Renal Clearance

    • Factors Affecting Hepatic Clearance

    • Capacity-Limited Elimination

    • Half-life

    • Drug Accumulation

  • Bioavailablity

    • Extent of Absorption

    • First-Pass Elimination

    • Rate of Aborption

  • Some Pharmacokinetic Equations

  • Placental Transfer

  • Redistribution

  • Drug-Plasma Protein Binding

  • Renal Clearance

• Drug Metabolism

  • Introduction

  • Phase I and Phase II Reaction Overview:

  • Phase I characteristics

  • Phase II characteristics

  • Conjugates

  • Principal organs for biotransformation

    • Sequence I

    • Sequence II

  • Bioavailability

  • Microsomal Mixed Function Oxidase System and Phase I Reactions

    • The Reaction

    • flavoprotein--NADPH cytochrome P450 reductase

    • Cytochrome P450: -- terminal oxidase

    • P450 Enzyme Induction

    • P450 Enzyme Inhibition

    • Human Cytochrome P450

  • Phase II Reactions

    • Toxicities

• Individual Variation in Drug Responses

• Genetic Factors in Biotransformation

• Effects of Age on Drug Responses

• Drug-Drug Interactions

Pharmacokinetics and some IV Anesthetics Agents

• Barbiturates

  • Thiopental

• Benzodiazepines

• Ketamine and Etomidate

• Propofol

• Opioids

  • Membrane Bilayer Structure

• 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

  • Generally inactive

    • Exception to the rule: morphine glucuronide metabolite-- more potent analgesic then parent compound

  • Rapidly excreted in the urine

  • High molecular weight conjugates:

    1. Excreted in the bile

    2. Conjugate bond may be cleaved by intestinal flora

    3. Parent drug released back to the systemic circulation

    4. This process, "enterohepatic recirculation":

       1. Delayed parent drug elimination

       2. Prolongation of drug effect

Principal Organs for Biotransformation:

• Principal Organ: Liver

  • Other metabolizing organs:

    • Gastrointestinal tract

    • Lungs

    • Skin

    • Kidney

• Sequence I

  1. Oral administration (isoproterenol (Isuprel), meperidine (Demerol), pentazocine (Talwain), morphine)

  2. Absorbed intact (small intestine)

  3. Transported first to the liver (portal system) and

  4. Extensive metabolism -- first-pass effect

• Sequence II

  1. Oral administration: (clonazepam (Klonopin), chlorpromazine (Thorazine))

  2. Absorbed intact (small intestine)

  3. Extensive intestinal metabolism -- contributing to overall first-pass effect

• Issues in bioavailability: reduced bioavailability

  • First pass effect: bioavailability of orally administered drugs -- so limited -- alternative routes of administration must be used

  • Intestinal flora may metabolize drugs

  • Unstable in gastric acid-- penicillin

  • Metabolized by digestive enzymes -- insulin

  • Metabolized by intestinal wall enzymes-- sympathomimetic catecholamines

Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61.

Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27

Mixed function oxidase System (cytochrome 450 System)--Phase I Reactions

• Microsomes have been used to study mixed function oxidases

  • Drug metabolizing enzymes:

    • Located in lipophilic, hepatic endoplasmic reticulum membranes

    • Smooth endoplasmic reticulum: contains enzymes responsible for drug metabolism

• The reaction:

  • One molecule oxygen is consumed per substrate molecule

  • One oxygen atom -- appears in the product; the other in the form of water

  • Oxidation-Reduction Process:

    • Two important microsomal enzymes:

      1. Flavoprotein--NADPH cytochrome P450 reductase

      2. Cytochrome P450: -- terminal oxidase

         1. Multiple forms

         2. Named cytochrome P450 because:

            • The reduced (ferrous) form, binds carbon monoxide: -- the resulting complex exhibits of absorption maximum at 450 nm.

• Cytochrome P450 Enzyme Induction:

  • Following repeated administration, some drugs induce cytochrome P450 (increase amount of P450 enzymes) usually by:

    • Increase enzyme synthesis rate

    • Reduced enzyme degradation rate

• Cytochrome P450 enzyme inhibition:

  • Certain drugs, by binding to the cytochrome component, act to competitively inhibit metabolism. Examples:

    •  Cimetidine (Tagamet) (anti-ulcer --H₂ receptor blocker) and Ketoconazole (Nizoral) (antifungal) bind to the heme iron a cytochrome P450, reducing the metabolism of:

      • Testosterone

      • Other coadministered drugs

      • Mechanism of Action: competitive inhibition

  •  Catalytic inactivation of cytochrome P450.

    •  Macrolide antibiotics (troleandomycin, erythromycin estolate (Ilosone)), metabolized by a cytochrome P450:

      • Metabolites complex with cytochrome heme-iron: producing a complex that is catalytically inactive.

    •  Chloramphenicol (Chloromycetin): metabolized by cytochrome P450 to an alkylating metabolite that inactivates cytochrome P450

    •  Other inactivators: Mechanism of Action: -- targeting the heme moiety:

      • Steroids:

        • Ethinyl estradiol (Estinyl)

        • Norethindrone (Aygestin)

        • Spironolactone (Aldactone)

      • Others:

        • Propylthiouracil

        • Ethchlorvynol (Placidyl)

Phase II Metabolism

• Overview: Phase II reactions:Non-microsomal enzymes

  • Reaction types:

    1. Conjugation

    2. Hydrolysis

    3. Oxidation

    4. Reduction

  • Location (non-microsomal enzymes): primarily hepatic (liver); also plasma & gastrointestinal tract

  • Non-microsomal enzymes catalyze all conjugation reactions except glucuronidation

• Conjugation reactions: Usually "detoxification reaction

• Conjugates:

  •  More polar

  •  Easily excreted

  •  Typically inactive

•  Conjugation:

  • Involves "high-energy" intermediates and specific transfer enzymes (microsomal or cytosolic transferases)

  •   Conjugation with glucuronic acid requires cytochrome P450 enzymes.

    • Glucuronic acid: available from glucose

    • Glucuronic acid conjugated to lipid-soluble drug results in lipophilic glucuronic acid derivative:

      • Pharmacologically inactive

      • More water-soluble; more easily excreted in urine & bile

  • Transferases:

    • Catalyzes coupling of an endogenous substance with a drug

      • Uridine-5'-diphosphate (UDP) derivative of glucuronic acid with a drug

    • Catalyzes inactivated drug within endogenous substrate

      • For example: S-CoA derivative of benzoic acid within endogenous substrate.

•  Toxicity:

  • Certain conjugation reactions: form toxic reactive species (hepatotoxicity)

    • Example:

      1. Acyl glucuronidation nonsteroidal antiinflammatory drugs

      2. N-acetylation of isoniazid

  •  Drugs metabolized to toxic products:

    • Acetaminophen hepatotoxicity -- normally safe in therapeutic doses

    • Therapeutic doses:

      • Glucuronidation + sulfation to conjugates (95% of excreted metabolites); 5% due to alternative cytochrome P450 depending glutathione (GSH) conjugation pathway

    •  At high doses:

      • Glucuronidation and sulfation pathways become saturated

      •  Cytochrome P450 dependent pathway: now more important

        • With depletion of hepatic glutathione, hepatotoxic, reactive, electrophilic metabolites are formed

        • Antidotes: N-acetylcysteine, cysteamine

          • N-acetylcysteine: protects patients from fulminant hepatotoxicity and death following acetaminophen overdose.