Pharmacokinetics: Distribution, Metabolism, and Excretion

Pharmacokinetics
Pharmacokinetic characteristics of drug molecules concern the processes of absorption,

distribution, metabolism, and excretion.
The bioavailability of a drug involves its permeation across cellular membrane barriers.
Drug permeation is dependent on:
 Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for most
drugs; however, water solubility can influence permeation through aqueous phases.
 Concentration gradient. Diffusion down a concentration gradient-only free drug forms
contribute to the concentration gradient.
 Surface area and vascularity. Important with regard to absorption of drugs into the
systemic circulation.
For weak acids and weak bases
 Ionized = Water soluble

 Nonionized = Lipid soluble
Ionization Many drugs are weak acids or weak bases and can exist in either nonionized or
ionized forms in an equilibrium.
Only the nonionized (uncharged) form of a drug crosses bio membranes.
Ionization increases renal clearance of drugs
Only free, unbound drug is filtered. Both ionized and nonionized forms of a drug are filtered.
Only nonionized forms undergo active secretion and active or passive reabsorption.
Ionized forms of drugs are "trapped" in the filtrate.
Acidification of urine → increases ionization of weak bases -→increases renal elimination.

Alkalinization of urine -→ increases ionization of weak acids -→ increases renal elimination.
ABSORPTION
Concerns the processes of entry of a drug into the systemic circulation from the site of its
administration. The determinants of absorption are those described for drug permeation.
Intravascular administration (e.g., IV) does not involve absorption, and there is no loss of drug.
With extravascular administration (e.g., per os [PO; oral], intramuscular [IM], subcutaneous
[SC], inhalation), less than 100% of a dose may reach the systemic circulation because of
variations in bioavailability.
1
First-Pass Effect. With oral administration, drugs are absorbed into the portal circulation and
initially distributed to the liver. For some drugs, their rapid hepatic metabolism decreases
bioavailability-the "first pass" effect.
DISTRIBUTION
The processes of distribution of a drug from the systemic circulation to organs and tissue involve
its permeation through membrane barriers and are dependent on its solubility (recall that only
nonionized drugs cross bio membranes), the rate of blood flow to the tissues, and the binding of
drug molecules to plasma proteins.
Plasma Protein Binding.
Many drugs bind to plasma proteins, including albumin, with an equilibrium between bound and
free molecules (recall that only unbound drugs cross bio membranes).
Competition between drugs for plasma protein binding sites may increase the "free fraction,"
possibly enhancing the effects of the drug displaced.
Special Barriers to Distribution
Placental: most small molecular weight drugs cross the placental barrier, although fetal blood
levels are usually lower than maternal
Blood-brain: permeable only to lipid-soluble drugs or those of very low molecular weight
METABOLISM
First-Pass Effect. With oral administration, drugs are absorbed into the portal circulation and
initially distributed to the liver. For some drugs, their rapid hepatic metabolism decreases
bioavailability-the "firstpass" effect.
The general principle of biotransformation is the metabolic conversion of drug molecules to

more water-soluble metabolites that are more readily excreted.
• In many cases, metabolism of a drug results in its conversion to compounds that have little or
no pharmacologic activity.
• In other cases, biotransformation of an active compound may lead to the formation of

metabolites that also have pharmacologic actions.
• A few compounds (prodrugs) have no activity until they undergo metabolic activation.
• Some compounds are converted to toxic metabolites, e.g., acetaminophen.
2
ELIMINATION
Concerns the processes involved in the elimination of drugs from the body (and/or plasma) and
their kinetic characteristics. The major modes of drug elimination are:
 Biotransformation to inactive metabolites

 Excretion via the kidney
 Excretion via other modes including the bile duct, lungs, and sweat
Zero-Order Elimination Rate
Rate of elimination is independent of plasma concentration (or amount in the body). A constant
amount of drug is eliminated per unit time; for example, if 80 mg is administered and 10 mg is
eliminated every 4 h, the time course of drug elimination is: Drugs with zero-order elimination
have no fixed half-life. Drugs with zero-order elimination include ethanol (except low blood
levels), phenytoin (high therapeutic doses), and salicylates (toxic doses).
First Order Elimination Rate
Rate of elimination is directly proportional to plasma level (or the amount present)-the higher the
amount, the more rapid the elimination. A constant fraction of the drug is eliminated per unit
time.
Most drugs follow first-order elimination rates
Time to eliminate 50% of a given amount (or to decrease plasma level to 50% of a former level)
is called the elimination half-life (t1/2).
Rate of elimination = glomerular filtration rate (GFR) + active secretion - reabsorption (active or
passive).
Filtration is a nonsaturable linear function. Ionized and nonionized forms of drugs are filtered,
but protein-bound drug molecules are not.
Clearance is defined as the volume of blood cleared of the drug in unit time. It represents the
relationship between the rate of drug elimination and its plasma level.

Pharmacokinetics: Distribution, Metabolism, and Excretion

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Pharmacokinetics

Pharmacokinetic characteristics of drug molecules concern the processes of absorption,

Drug permeation is dependent on:

For weak acids and weak bases

 Ionized = Water soluble

Only the nonionized (uncharged) form of a drug crosses bio membranes.

Ionization increases renal clearance of drugs

Ionized forms of drugs are "trapped" in the filtrate.

Acidification of urine → increases ionization of weak bases -→increases renal elimination.

Plasma Protein Binding.

Special Barriers to Distribution

The general principle of biotransformation is the metabolic conversion of drug molecules to

• In other cases, biotransformation of an active compound may lead to the formation of

• Some compounds are converted to toxic metabolites, e.g., acetaminophen.

 Biotransformation to inactive metabolites

Zero-Order Elimination Rate

First Order Elimination Rate

Most drugs follow first-order elimination rates

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