Pharmacokinetics

Most excretion occurs in kidneys

Drug clearance rate via renal greatly differ

Most drugs excreted in urine or bile (lesser extent)

Enterohepatic circulation

Account up to 20% of total drug in the body

Results in prolonged drug action

Drugs may be excreted in the bile after transport by the solute carriers and ABC transporters

Glomerular ultrafiltration

Level of plasma protein binding to drug

Plasma proteins too large to
pass renal luminal barrier

Retained in circulation

Drugs with high affinity protein slower excretion

Less free drug for filtration and diffusion

Small molecules readily pass and are cleared

Unbound fraction exhibits pharmacologic effects

Mode of secretion

Highly lipophilic drugs or non-ionized
absorbed via passive diffusion

Tubular secretion involve specific transporter proteins

Urine pH

pH of urine can change dramatically

Due to diet or drug intake

Artificial alteration of pH is used to
increase excretion of certain drugs

Ion trapping to increase drug retention in urine

Acidic urine increases basic drug excretion

Alkaline urine increases acidic drug excretion

Plasma clearance

Indicator of efficiency of drug removal from plasma

Clearance is a constant for any given drug

Volume of blood cleared of a drug through an organ per time

Drug excretion by liver or kidneys is best described by clearance

Reduced clearance

Indicative of function impairment of excretory organ

Drug elimination

Measure of loss of drug mass from the circulation per unit of time

Includes loss of drug by metabolism and any other excretory routes

Movement of drugs into and out of the body strongly influenced by:

Drug lipid solubility

Drug pKa

pH of the compartment

Absorption reservoir

Plasma, body fat and interstitial water

Transcellular water ~2%

Comprises CSF, intraocular, peritoneal, pleural and synovial fluids and digestive secretions

Plasma water ~5%

Interstitial water ~16%

Intracellular water ~35%

Fat ~20%

Apparent volume of distribution (Vd)

Dose divided by measured plasma concentration

Gives estimate where drug is (tissues or circulation)

Drug with very low Vd likely to still be in circulation

Large Vd drug likely to enter body compartment

Endothelial cells

Fenestrations

Gaps that allow solute diffusion

Blood brain barrier

Molecule must pass through at least 2 membranes

Highly lipophilic drugs able to readily pass through

Active transport by carriers

AA, glucose, amines and purines

Diffusion is PRIMARY for drugs crossing BBB

Phase 1

Oxidation (also reduction and hydrolysis)

Mediated by cytochrome system associated with ER

Most common residue is hydroxyl

Mainly in liver

Hepatic cytoplasmic microsomal enzymes

E.g. cytochrome systems

Can also occur in other tissues or plasma

Nonpolar drugs go through phase 1 more than polar

Need to cross cell membrane to reach cytochrome systems

Cytochrome system

3 main CYP gene families

CYP1

CYP2

CYP3

Net effect of cytochrome p450 cycle
is addition of oxygen or hydroxyl

Genetic variations exist

Primary cause of patient response variation

P450 enzyme levels regulated by external factors

E.g. grapefruit juice and Brussels sprouts

Metabolic enzymes generally alter drugs to activate them and make them more water soluble

Phase 2

Mainly in the liver

Can also occur in other tissues like lungs and kidneys

Involves altering drug structure

Reduce intrinsic efficacy for excretion

Normally results in inactive product (some exceptions)

Conjugation of site chains

Glucuronidation

Sulphation

Glutathione addition

Methylation

Glycine or water addition

Produces polar molecule ready for excretion

Bioavailability

Amount of drug reaching the systemic circulation

First pass effect

Almost all drugs entering the body from the GI tract

Occur in gastric mucosa or liver

Reduces bioavailability prior to systemic circulation

Pro-drugs

Inactive drug precursor

Gain full drug activity after metabolic processing

Higher activity

Different absorption or distribution properties than precursors

Drug properties

Lipid solubility

Too lipid-soluble = retained in membrane

High soluble = higher membrane penetration

Ionization state

Ionized dissolve aqueous fluids than uncharged

Dissociation constant

Ratio between dissociated ions and drug

Negative value = greater proportion
of non-ionized drug

Greater lipid solubility

Acidic drug will accumulate in HIGH pH

Basic drug will accumulate in LOW pH

Ion Trapping

Drug's ionization preference and retention

Active transport

Specific carriers

ABC transporters

Specialized membrane proteins

Transport AGAINST concentration gradients

E.g. P‐glycoprotein transporters

Primary group of ABC transporters

Mediate removal of drugs from cells

Pinocytosis

Passive movement

Diffusion is the mechanism used by most drugs

Facilitated diffusion is passive with no energy

Aquaporins

Solute carrier

Facilitates transport single species IN THE DIRECTION of its electrochemical gradient

E.g. Organic cation transporters

Mediate the movement of dopamine and choline