Dr. Robert G. Lamb Professor Pharmacology & Toxicology
Definition of Drug Absorption
Plasma Drug Bound To Plasma Protein
Drug absorption is the movement of the drug from its site of administration into the bloodstream.
Definition of Bioavailability
Bioavailability (F) is the fraction of administered drug thatreaches the systemic circulation. Bioavailability is 1 (100% absorption) for intravascular drug administration and usually less than 1 for oral drug administration. Drug Bioavailability is a key factor in the onset of drug Action.
Model of Membrane Structure
Lipid-Globular Protein Mosaic Model of Membranes Outside - High Ca2+ and Na+, positive charge
Diffusion Filtration CarrierMediatedReceptorMediated Endocytosis
+ + + + + + +
Inside - Low Ca2+ and Na+, high K+, negative charge
Fick’s Law of Passive Diffusion
DIFFUSION RATE = - DAK (Cout-Cin) / ∆X Diffusion Constant (D) is inversely proportional to drug’s weight. Area (A) of the membrane. Lipid partition coefficient (K), a measure of lipid solubility. Cout - Cin is concentrationgradient across membrane (downhill). ∆X thickness of membrane.
pH = pKa + log Base[A- ; B] / Acid[HA; BH+] weak acids = [HA ↔ H+ + A-] weak bases = [B + H+ ↔ BH+] Acid is a proton donor Base is a proton acceptor
H-H equation is used to calculate the percent ionization of a drug in cellular compartments of different pH. Understanding how changes in pH alter theionization of drugs is very important since unionized drugs cross membranes.
Percent Ionization of Aspirin [Blood] Percent Ionization of Aspirin [Stomach]
pKa of Aspirin [weak acid] = 3.4 (50% HA and A- at pH 3.4) pH stomach = 1.4 pH blood = 7.4 Stomach (pH=1.4) Blood (pH=7.4) pH - pKa = log (A-)/(HA) 7.4 – 3.4 = 4 log of 10,000 = 4 (blood)
pH = pKa + log (A-)/(HA) [ H-H equation] pH - pKa= log (A-)/(HA) 1.4 – 3.4 = - 2 log of 0.01= -2 (stomach)
A- / HA= 10,000/ 1 so A- is 10,000 fold greater than HA Stomach Blood [Blood/Stomach] A- + HA ↔ HA + A[.01] +   + [10,000] 10,000/1 Aspirin is readily absorbed from stomach into blood.
A- / HA= 0.01/ 1 so HA is 100 fold greater than AHA moves from the stomach into the blood (good absorption)
Percent Ionization of Codeine[Stomach]
CODEINE (weak base) pKa = 7.9 Stomach pH=1.9 Blood pH =7.4
pH 3 units > pKa 2 units > pKa
Percent Ionization of Drugs
Weak Acids % ionization of aspirin 99.9% log [A-/HA = 1000/1] 99% log [A-/HA = 100/1] Weak Bases % ionization of codeine 0.1% 1% 9% 50% 90.9% 99% 99.9% log [B/BH+ = 1000/1] log [B/BH+ = 100/1] log [B/BH+ = 10/1] log [B/BH+ = 1/1] log [B/BH+ = 1/10] log [B/BH+ = 1/100]log [B/BH+ = 1/1000]
pH - pKa = log(B)/(BH+) [H-H equation] 1.9 - 7.9 = -6 log 0.0000001 = -6 [Stomach] B/ BH+ = 0.000001/1 so BH+ is 1,000,000 fold greater than B. Little B (codeine) is absorbed into the blood (poor absorption)..
1 unit > pKa pH = pKa 1 unit < pKa 2 units < pKa 3 units < pKa
90.9% log [A-/HA = 10/1] 50% 9% 1% 0.1% log [A-/HA = 1/1] log [A-/HA = 1/10] log [A-/HA = 1/100]log [A-/HA = 1/1000]
Membrane Transport Processes Site-Specific Drug Delivery
OUTSIDE Solute B Solute X MEMBRANE B X X Solute Y CY C CY Y X B INSIDE B B
Filtration Passive Diffusion Facilitated Diffusion Active Transport Receptor-Mediated Endocytosis
Radioactive Iodine to treat thyroid disorders. Liposome entrapped drugs taken up by liver and spleen.
Solute ZC1Z A
Kinetics of Transport Processes Enteral Drug Administration
Linear Kinetics Filtration Passive Diffusion
Drug absorption from mouth throughout gastrointestinal tract. Advantages: safe, economical Disadvantages: slow onset, noncompliance, low bioavailability
Saturation Kinetics Facilitated Diffusion Active Transport Receptor-Mediated...