59-291 Section 1, Lecture 2 PHARMACOKINETICS [DRUG] [DRUG] IN BODY FLUIDS OR TISSUES OVER TIME Depends on rates of: -drug absorption -drug distribution -drug elimination= rates of biotranformation + excretion

Figure 2-4 Drug transport in the body. (From McKenry, L. M Figure 2-4 Drug transport in the body. (From McKenry, L. M., & Salerno, E. 1995. Mosby’s pharmacology in nursing, 19th ed. St. Louis, MO: Mosby.)

Drug absorption Rate of drug absorption- passage of the drug from its site of administration into the circulation Exception-Topically administered drugs (examples ) are absorbed directly into target tissues.

Two suggested models show the relationship of plasma drug concentration to the rate of drug absorption, distribution and elimination. K: rate constant C: conc. D: amount of drug in body at that time V: volume of the compartment

Most drugs cross biomembranes by passive diffusion where the rate of absorption is proportional to the drug concentration gradient. In which case will the rate be larger? Out In A B

Passive diffusion Aqueous diffusion Drug passes through aqueous pores in biomembranes BUT these pores limited to molecular wts of <40 Lipid Diffusion -drug if hydrophopic and uncharged dissolves in lipid (hydrophobic components) of biomembranes

A few drugs are imported via active transport (against a concentration gradient) by facilitated diffusion with the aid of specific membrane transport proteins e.g. Cephaloporins that are absorbed by a transporter for dipeptides

Effect of pH on the absorption of weak acids and bases -many drugs are weak acids or bases -Only non-ionized (i.e. no charge) form of drugs is soluble in lipid membrane and can get across Weak acids (HA) donate a proton (H+) to form anion (A-), whereas weak base (B) accept a proton to form cations (HB+) Drugs that are weak acids: HA H+ + A- Drugs that are weak bases: BH+ H+ + B Which form can get across the membrane?

Henderson-Hasselbalch equation can be used to determine the ratio of nonprotonated to protonated pH = pKa + log [nonprotonated]/[protonated] pKa: pH at which the protonated and non-protonated forms are equal if pKa >7 weak base; if pKa <7 weak acid If pH<pKa protonated form>non-protonated form

if pKa >7 weak base; if pKa <7 weak acid pH Stomach 1-2 Weak acids are more absorbed Small intestine 6-7 Weak bases are more absorbed if pKa >7 weak base; if pKa <7 weak acid

Example: Salicylic acid pKa=3 At a pH of 2 pH = pKa + log [nonprotonated]/[protonated] 2= 3 + log [nonprotonated]/[protonated] -1 =10-1 = 0.1 = 1/10 = log [nonprotonated]/[protonated] For a weak acid which form is uncharged? 10 1

Amphetamine- pKa =10 does it get absorbed in the stomach where the pH= 2? pH = pKa + log [nonprotonated]/[protonated] 2= 10 + log [nonprotonated]/[protonated] -8 = log [nonprotonated]/[protonated] 10-8 = 0.00000001 = 1/100,000,000= [nonprotonated]/[protonated] For a weak base which form is uncharged? 100,000,000 1

Amphetamine- pKa =10 does it get better absorbed in the intestine where the pH= 7? pH = pKa + log [nonprotonated]/[protonated] 7= 10 + log [nonprotonated]/[protonated] -3 =log [nonprotonated]/[protonated] 1/1000= [nonprotonated]/[protonated] The ratio of two forms at a particular site influences the rate of drug absorption, distribution or elimination