• Equilibration: the measured amount of drug in the blood has a relationship to amount of drug in the rest of the body
• Can’t directly determine drug concentration at site of action, but plasma concentration correlates with drug concentration if completely distributed
• we assume the drug in the plasma equilibrates (or know at least where we are in relation to its equilibration if plasma concentration is measured rapidly after administering dose or if the distribution kinetics is abnormally slow)
• Plasma total drug µ plasma free drug
• plasma concentration measured is total drug present in plasma (sum of free drug and drug bound to plasma proteins)
• free drug equilibrates to active sites in tissue, but concentration of total drug is proportional to concentration of free drug and therefore accurately reflects drug concentration at active sites within tissue
• any bound drug (to tissues or even albumin) is no longer considered an active part of the drug
• amount of drug bound to plasma proteins will change if: change level of plasma protein or change in binding occurs

• Time in which a constant fraction of the drug is absorbed and/or eliminated
• begin with 100mg of drug ‘X’ and eliminate a constant fraction of 10%: 100mg Þ 90mg Þ 81mg Þ 72.9 Þ etc
• will never reach 0mg since we are eliminating a fraction of the total each time Þ same fraction but less drug with time
• Method of absorption and elimination for most drugs
• Mathematics:
• D/T = -K_a(D) Þ D = D_o(e^-KaT) Þ Ln(D/D_o) = -K_aT Þ at T½, Ln(D/D_o) = Ln(1/2) = -0.693 so T½ = .693/K_a

• Time in which a constant amount of the drug is absorbed and/or eliminated
• EtOH eliminated 1^st order Þ EtOH metabolized and a certain fraction is eliminated with time Þ consume so much EtOH that the metabolic enzymes become saturated Þ all enzymes are eliminating a constant amount Þ 0 order

Pharmacokinetic Parameters – parameters useful in predicting plasma concentration that develops on a dose regimen

• bioavailability (F_o): fraction of an orally administered dose that enters the systemic circulation
• F_o = (AUC-oral) / (AUC-IV) = (0-1)/1 so ranges between 0 and 1 (AUC = area under the curve)
• Give drug IV, now give same dose orally Þ F_o ß so need to Ý dose to achieve same effect so must know F_o
• volume of distribution (V_D): assume plasma drug concentration is proportional to total body concentration but not equal to it
• V_D is needed since we can only measure the plasma
• V_D = virtual volume (not a real volume) = the apparent fluid volume the drug would be in if we had that much volume
• For 70kg man: total fluid vol = 40L; plasma vol = 4L; Xtracell fluid vol = 15L
• If drug is between 40-70L, then it’s distributed throughout the fluid of the body
• If drug is 200L Þ must be in tissues some 3x more than in the plasma (DDT = 2000 L so much more in tissues)
• clearance (Cl): fraction of drug eliminated per unit time
• Inulin: not reabsorbed, metabolized, secreted so GFR = Cl_inulin = 130ml/min
• Cl of glucose = 0 Þ totally reabsorbed
• Cl of PCN or PAH = 650ml/min Þ actively secreted and not reabsorbed
• Cl of acetominophen = very low Þ metabolized drug (cleared by liver)
• Cl total = Cl kidney + Cl liver + Cl other
• half-life (T½): time required for the elimination of half of the drug present
• with 1^st order kinetics, a constant fraction is lost per unit time: ½ left after 1 half-life; ¼ left after 2 ; 1/8 left after 3; etc
• T½ for absorption = 0.693/Ka; T½ for elimination = 0.693/Ke

• Loading Dose:
• C_o = (F_oD)/V_D : (use D/T instead of D when worried about how often your giving the drug)
• can estimate the initial concentration that develops after administration of a single dose of drug so this is a way to figure out what mass of drug to give in order to achieve a certain blood level
• dependent on the volume of distribution
• absorption is much faster than elimination so Cl is not needed
• Maintainance Dose:
• (D/T) x F_o = Cl x C_ss
• way to measure steady state of drug in plasma: steady state Þ IN = OUT
• IN = some dose per unit time = (D/T) x F_o Þ mass/time
• OUT = Cl x C_ss (steady state conc) Þ mass/time
• Steady state dependent only on Cl, not what volume its in
• Half-Life:
• T½ = (0.693 x V_D)/Cl
• determine how long it takes to get rid of drug and the rate at which steady state is achieved; a small clearance and large vol. of distribution will increase drug half-life
• T½ = 0.693/Ke and Ke = Cl/V_D (fraction of drug eliminated moment by moment) Þ T½ = (0.693 x V_D) / Cl

• When administering a chronic dose, clearance is not changing but concentration of drug is increasing in a fixed volume
• Drug concentration continues to increase until a steady state is reached Þ takes ~4 half-lives to reach steady state
• Once reached, concentration constantly dips above and below the steady state Þ goal is to minimize the swing in concentration
• If drug has large swing, chance of sampling blood at either the peak or trough resulting in great variability in concentration
• Want consistent concentration upon blood draws
• 
• Consequences of missing a dose
• Will take 4 half-lives to get back to steady state
• If drug has wide swings, then missing dose can potentially cause the blood concentration to reach zero Þ bad
• Can also potentially take drug out of effective therapeutic range Þ bad
• What if you cant wait 4 half-lives to reach steady state
• If IV: give amt you want in blood and calculate maintenance dose Þ reach steady state in minutes
• If Oral: give loading dose to reach steady state Þ still takes 4 half-lives to get back to steady state but drug is already within therapeutic window after one dose