Principles of Pharmacokinetics Part Two

Principles of Pharmacokinetics Part Two Bioavailability • Bioavailability is the fraction/percentage of a given dose of a drug that gains access to the systemic circulation, where it dissolves (giving drug concentration) and can produce therapeutic effects • Bioavailability is 100% following intravenous injection – there are no losses • For orally given drugs, bioavailability depends on: o Rate of absorption form the gastrointestinal system o Rate of first pass metabolism in the liver • E.g. nitroglyceride (oral) has a low bioavailability due to rapid first pass metabolism • E.g. Fosamax for osteoporosis has a low bioavailability due to very poor absorption Absolute bioavailability (factor F) • Absolute bioavailability is measured by: o Comparing intravenous administration (iv) and oral administration o F = AUC oral / AUC iv ▪ D: dose, AUC: area under the ‘plasma vs time’ curve • Relative bioavailability: comparing different dosage forms, different routes or different conditions Bioequivalence • New product can market if it shows bioequivalence to conventional drug(s) • Important parameters: AUC, Cmax (maximum plasma concentration) and Tmax (time required to achieve the maximum plasma concentration) ‘Apparent’ volume of distribution • Volume of distribution – measure of the apparent space in the body available to contain the drug • Apparent volume of distribution (Vd): volume of fluid required to contain the total amount (Q) of drug in the body at the same concentration as the drug is present in the plasma, Cp: o Vd = Q/Cp Volume of distribution – measure of the apparent space in the body available to contain the drug • Volume of Distribution (Vd): the amount of drug in the body divided by the concentration in the blood o Drugs that are highly lipid soluble (e.g. digoxin) have a very high volume of distribution (500L) o Drugs that are lipid insoluble (e.g. neuromuscular blockers) remain in the blood, have a low Vd • Apparent volume distribution: volume of fluid required to contain the total amount (Q) of a drug in the body at the same concentration as the drug is present in the plasma (Cp) → Drugs confined to the plasma compartment (0.051 L/Kg) - Strongly plasma protein-bound or very large molecules (e.g. dye, heparin) → Vd < 5L → Drugs distributed in the extracellular compartment (0.21 L/kg) Water-soluble molecules (e.g. gentamicin) – cannot enter cells or cross barriers due to low lipid solubility → 5L < Vd < 20 L → Drugs distributed throughout the total body water (0.55 L/kg) - Drugs relatively lipid soluble, can cross cell membrane → 20L < Vd < 40 L → Drugs distributed to (and concentrated in) peripheral tissue - Partitioning into body fat (e.g. thiopentone, 0.2-0.35 L/kg), and bone (e.g., Ca2+ ions) can further increase volume of distribution → Vd > 40 L (exceeds total body volume) Multiple oral dosing and blood concentrations • Steady-state concentration: rate of input is equivalent to rate of output • It - • • normally takes 4-5 t1/2 (half-lives) to reach steady state Ideally in drug treatment, a steady-state plasma concentration is required within the minimum effective concentration (mec) and the maximum safe concentration (msc) Loading dose or priming dose for drugs that have a longer half-life – giving an initial higher dosage to administer the drug more quickly Single compartment model • For many drugs, the volume of distribution (volume from which drug is excreted) appears to be a single entity in terms of drug concentrations vs. time • These drugs are consistent with the one compartment model where the whole body is considered as a single well-stirred compartment • Linear relationship in semilogarithmic plot of concentration in plasma (Cp) vs. time Two compartment model • Some drugs equilibrate with different tissues at different rates • Body is considered to consist of central + peripheral compartment • Comprises a fast (alpha) and slow (beta) phase • Fast phase: redistribution of drug between central and peripheral compartments Rate of reaction • E.g. ethanol if consumed: (1) ≤ 8g/hr follows 1st order kinetics, (2) > 8g/hr follows zero order kinetics → limited number of enzymes becomes saturated by excess quantities of ethanol