Volume of Distribution (Vd) Volume of distribution (Vd) relates amount of drug in body to plasma concentration Vd = (amount of drug in the body) / (plasma drug concentration) Vd is changed in disease states that decrease plasma proteins a decrease in plasma proteins decreases binding of drug to plasma proteins ↑ Vd of drugs e.g., liver disease via ↓ protein synthesis e.g., kidney disease via urinary protein loss Vd increased in disease states that increase total body water ascites, pulmonary edema, heart failure can lower plasma concentration of water soluble drugs Vd predicts drug distribution in body low Vd drugs 4-8 L drugs distribute in vascular compartment (blood) and bind plasma proteins drugs are large and/or charged molecules medium Vd drugs drugs distribute in extracellular compartment and/or total body water drugs are small, hydrophilic molecules that do not bind plasma proteins high Vd drugs > body weight drugs distribute in all tissues drugs are small, lipophilic molecules that bind strongly to extravascular proteins Clearance (CL) CL = (rate of elimination of drug) / (plasma drug concentration) = Vd * Ke Ke = elimination constant CL relates the rate of elimination to the plasma concentration Half-Life (t1/2) t1/2 = (0.7 * Vd)/CL half-life is time required for amount of drug to fall to 50% of an earlier measurement during elimination or during constant infusion a drug infused at a constant rate reaches about 94% of steady state after 4 half lives for drugs eliminated by first-order kinetics, half-life is constant regardless of concentration # of half lives 1 2 3 4 Concentration 50% 75% 87.5% 93.75% Bioavailability (F) bioavailability is the fraction of administered dose that reaches systemic circulation bioavailability is defined as unity, or 100%, in case of IV administration bioavailability of drug administered by other routes is generally reduced by incomplete absorption, first-pass metabolism, and any distribution into other tissues that occurs before the drug enters systemic circulation e.g., orally, F = percent that is absorbed and survives first-pass metabolism in liver Calculation of bioavailabillity (F) = 100% * (AUC-oral * Dose-IV) / (AUC-IV * Dose-oral), where AUC is the area under the curve of a pharmacokinetic plasma concentration versus time plot delayed release formulations will have slower rise and lower peak compared with rapid release formulations