Pharmacokinetics

ADME

• Absorption: drug enters the plasma

• Distribution: drug travels through the body

• Metabolism: drug is modified by the body

• Elimination: drug leaves the body

Routes of Administration

• Parenteral

  • Intravenous (IV)

    • most dangerous, most invasive

  • Intramuscular (IM)

  • Subcutaneous (SQ)

  • Intradermal (ID)

• Enteral

  • Per Os (PO)

    • the safest rout of absorption

  • Sublingual (buccal)

• Other

  • ocular, inhalation, nasal, intrathecal/intraventricular, transdermal, rectal

Absorption

• Mechanisms

  • Passive diffusion: lipid soluble substances and small water soluble substances able to diffuse membrane easily

    • high concentration → low concentration

  • Facilitated diffusion: water soluble substances require concentration gradient and carrier molecule

  • Active transport: requires a carrier protein and ATP to move against a concentration gradient

  • Endocytosis: also requires ATP for large molecules

• Influences

  • pH

  • blood flow

  • surface area

  • time

  • P-glycoprotein

• Bioavailability

  • rate and extent that a drug reaches systemic circulation

  • affected by: first pass metabolism, solubility, stability, and formulation

• Other

  • Bioequivalence: show comparable bioavailability and peak plasma concentration

  • Therapeutic equivalence: pharmaceutically equivalent (same dosage, conc., RoA) and bioequivalence

Distribution

• drug enters interstitial space and intracellular space

• blood flow (vascular vs. avascular tissues)

• capillary permeability

  • blood-brain barrier

  • hepatic sinusoids

• protein bindging

  • plasma proteins

  • tissues proteins

• lipid solubility

• (Apparent) Volume of Distribution

  • volume required to contain the entire amount of drug at the plasma concentration

    • V_d = amount of drug/initial concentration

  • fluid compartments

    • 60% water (600 ml)

      • 40% ICF (400 ml)

      • 20% ECF (200 ml)

        • 16% interstitial fluid (160 ml)

        • 4% plasma (40 ml)

  • apparent because drug is not always evenly distributed

    • lipid and protein drugs love to hide

  • useful in calculating a loading dose

  • higher the apparent volume of distribution, longer the time for clearance

Clearance: the volume of plasma that is cleared of drug over time

• half-life: the time require for the amount of drug in the body to be reduced by half

  • plasma concentration to be cut in half

• zero-order kinetics: a constant amount of drug is removed over a unit of time

  • only applies when system is fully saturated

• first order kinetics: a constant fraction of drug is removed over a unit of time

  • remove 25% at a time

• Clearance of drug = 0.693 x v_d/t_1/2

• Kinetics of Metabolism

  • first-order kinetics: v = V_max[C]/k_m

  • zero-order kinetics: v = V_max[C]/[C]

Metabolism

• main goal: increase water solubility

  • allows for renal elimination

  • metabolizes in the kidneys and liver

• phase I: make lipophilic drug more polar by oxidation, reduction, and/or hydrolysis

  • drug may be activated, unchanged, or inactive

  • increase polarity by adding -OH or -NH₂

  • runs through cytochrome P450 system

    • in mitochondria and ER

  • specificity: drugs may be metabolized by several different isoforms of CYP

  • genetics: individual/race usually decrease rate of metabolism

  • induction: certain compounds induce the metabolism of others by enhancing CYP

  • inhibition: certain compounds inhibit the metabolism

  • other reactions: amine oxidation, alcohol dehydrogenation, esterases, hydrolysis

• phase II: turns drug into conjugation product that is water soluble

  • added to -OH, -NH₂, or -COOH grooups

  • usually decreases or inactivates drugs

  • reactions: glucuronidation (most common), sulfonation, acetylation

  • increases water solubility and therefore elimination

• Renal Clearance

  • glomerulus: passive filtration system

  • proximal tubule: actively secretes some drugs

  • distal tubule: passively reabsorbs lipid soluble drugs

• other routes: GI and pulmonary

• alteration of half-life

  • renal impairment

  • hepatic impairment

  • heart failure

  • thyroid dysfunction

Dosage Regimens

• Goal is to achieve steady state concentration

  • rate of elimination = rate of administration

• IV infusion

  • as the rate of infusion increase, the rate of elimination increase (1st order)

  • rate of infusion does not determine when steady state is reached, but what plasma concentration is reached

    • steady state is achieved at 5 half lives

      • 1 = 50%, 2 = 75%, 3 = 90%, 4 to 5 = 100%

Fixed dose/fixed time

• the goal is steady state

• changes in dosing frequencies

  • changes the peaks and troughs

  • does not change the time to steady state

  • does not change the average plasma

• oral

  • has a slower absorptive phase

    • affected by rate of absorption and rate of elimination

  • still has the same time to steady state

Optimization of dose

• goal: maximize therapeutic effect while minimize toxicity

• doing rate = (plasma)(CL)/F

• loading dose

  • decrease time to therapeutic range

  • oral: loading dose = V_d x C_p/F

  • IV: loading dose = V_d x C_p

• dose adjustment

  • requires therapeutic drug monitoring

  • additional dosage needed

  • V_d (C₂ - C₁)