Pharmacokinetics

Chapter 1 Pharmacokinetics

I. General (Fig. 1-1)

A. Pharmacokinetics is the fate of drugs within the body.

B. It involves drug:

1-1 Schematic representation of the fate of a drug in the body (pharmacokinetics). Orange arrows indicate passage of drug through the body (intake to output). Orange circles represent drug molecules. RBC, red blood cell.

ADME− Absorption, Distribution, Metabolism, Excretion

II. Drug Permeation

• Passage of drug molecules across biological membranes

• Important for pharmacokinetic and pharmacodynamic features of drugs

A. Processes of permeation (Fig. 1-2)

1. Passive diffusion

a. Characteristics

(1) Does not make use of a carrier

(2) Not saturable since it doesn’t bind to a specific carrier protein

(3) Low structural specificity since it doesn’t require a carrier protein

(4) Driven by concentration gradient

1-2 Overview of various types of membrane-transport mechanisms. Open circles represent molecules that are moving down their electrochemical gradient by simple or facilitated diffusion. Shaded circles represent molecules that are moving against their electrochemical gradient, which requires an input of cellular energy by transport. Primary active transport is unidirectional and utilizes pumps, while secondary active transport takes place by cotransport proteins.

(From Pelley JW and Goljan EF. Rapid Review Biochemistry, 2nd ed. Philadelphia, Mosby, 2007, Figure 3-1.)

Passive diffusion driven by concentration gradient.

b. Aqueous diffusion

(1) Passage through central pores in cell membranes

Aqueous diffusion via pores in cell membranes.

(2) Possible for low-molecular-weight substances (e.g., lithium, ethanol)

c. Lipid diffusion

(1) Direct passage through the lipid bilayer

• Facilitated by increased degree of lipid solubility

(2) Driven by a concentration gradient (nonionized forms move most easily)

(3) Lipid solubility is the most important limiting factor for drug permeation

• A large number of lipid barriers separate body compartments.

(4) Lipid to aqueous partition coefficient (PC) determines how readily a drug molecule moves between lipid and aqueous media.

High lipid-to-oil PC favors lipid diffusion.

Most drugs are absorbed by passive diffusion.

2. Carrier-mediated transport

a. Transporters are being identified and characterized that function in movement of molecules into (influx) or out (efflux) of tissues

• See Tables 3-1; and 3-2 of Biochemistry Rapid Review for further details on the movement of molecules and ions across membranes.

b. Numerous transporters such as the ABC (ATP-binding cassette) family including P-glycoprotein or multidrug resistant-associated protein type 1 (MDR1) in the brain, testes, and other tissues play a role in excretion as well as in drug-resistant tumors.

Carrier-mediated transport is mediated by influx and efflux transporters.

c. Characteristics of carrier-mediated transport

(1) Structural selectivity

(2) Competition by similar molecules

Drug competition at transporters is a site of drug-drug interactions.

(3) Saturable

d. Active transport

(1) Energy-dependent transporters coupled to ATP hydrolysis (primary active transport); others take place by cotransport proteins (secondary active transport)

(2) Movement occurs against a concentration or electrochemical gradient

(3) Most rapid mode of membrane permeation

(4) Sites of active transport

(a) Neuronal membranes

(b) Choroid plexus

(d) Hepatocytes

Active transport requires energy to move molecules against concentration gradient.

e. Facilitated diffusion

(1) Does not require energy from ATP hydrolysis

(2) Involves movement along a concentration or electrochemical gradient

(3) Examples include: movement of water soluble nutrients into cells

(a) Sugars

(b) Amino acids

(d) Pyrimidines

Sugars, amino acids, purines, pyrimidines and L-dopa by facilitated diffusion

3. Pinocytosis/endocytosis/transcytosis

a. Process in which a cell engulfs extracellular material within membrane vesicles

b. Used by exceptionally large molecules (molecular weight >1000), such as:

(1) Iron-transferrin complex

(2) Vitamin B₁₂-intrinsic factor complex

III. Absorption

• Absorption involves the process by which drugs enter into the body.

A. Factors that affect absorption

1. Solubility in fluids bathing absorptive sites

a. Drugs in aqueous solutions mix more readily with the aqueous phase at absorptive sites, so they are absorbed more rapidly than those in oily solutions.

b. Drugs in suspension or solid form are dependent on the rate of dissolution before they can mix with the aqueous phase at absorptive sites.

2. Concentration

• Drugs in highly concentrated solutions are absorbed more readily than those in dilute concentrations

3. Blood flow

a. Greater blood flow means higher rates of drug absorption

b. Example−absorption is greater in muscle than in subcutaneous tissues.

4. Absorbing surface

Blood flow to site of absorption important for speed of absorption.

a. Organs with large surface areas, such as the lungs and intestines, have more rapid drug absorption

b. Example−absorption is greater in the intestine than in the stomach.

Drugs given intramuscularly are absorbed much faster than those given subcutaneously.

Absorbing surface of intestine is much greater than stomach.

5. Contact time

• The greater the time, the greater the amount of drug absorbed.

6. pH

a. For weak acids and weak bases, the pH determines the relative amount of drug in ionized or nonionized form, which in turn affects solubility.

b. Weak organic acids donate a proton to form anions (Fig. 1-3), as shown in the following equation:

1-3 Examples of the ionization of a weak organic acid (salicylate, top) and a weak organic base (amphetamine, bottom).

where HA = weak acid; H⁺ = proton; A⁻ = anion

Weak organic acids are un-ionized (lipid soluble form) when protonated.

c. Weak organic bases accept a proton to form cations (see Fig. 1-3), as shown in the following equation:

where B = weak base; H⁺ = proton; HB⁺ = cation

Weak organic base are ionized (water soluble form) when protonated.

d. Only the nonionized form of a drug can readily cross cell membranes.

e. The ratio of ionized versus nonionized forms is a function of pK_a (measure of drug acidity) and the pH of the environment.

(1) When pH = pK_a, a compound is 50% ionized and 50% nonionized

(2) Protonated form dominates at pH less than pK_a

(3) Unprotonated form dominates at pH greater than pK_a.

(4) The Henderson-Hasselbalch equation can be used to determine the ratio of the nonionized form to the ionized form.

f. Problem: Aspirin is a weak organic acid with a pKa of 3.5. What percentage of aspirin will exist in the lipid soluble form in the duodenum (pH = 4.5)?

• Solution:

and

Weak organic acids pass through membranes best in acidic environments.

Weak organic bases pass through membranes best in basic environments.

IV. Bioavailability

• Bioavailability is the relative amount of the administered drug that reaches the systemic circulation.

• Several factors influence bioavailability.

Bioavailability depends on the extent of an orally administered drug getting into the systemic circulation

A. First-pass metabolism

• Enzymes in the intestinal flora, intestinal mucosa, and liver metabolize drugs before they reach the general circulation, significantly decreasing systemic bioavailability.

Sublingual nitroglycerin avoids first-pass metabolism, promoting rapid absorption.

B. Drug formulation

• Bioavailability after oral administration is affected by the extent of disintegration of a particular drug formulation.

Slow release formulations are designed to extend the time it takes a drug to be absorbed so that the drug can be administered less frequently.

C. Bioequivalence

1. Two drug formulations with the same bioavailability (extent of absorption) as well as the same rate of absorption are bioequivalent.

2. Must have identical:

a. T_max (time to reach maximum concentration)

b. C_max (maximal concentration)

c. AUC (area-under-the-curve from concentration versus time graphs)

Bioequivalence depends on both rate and extent of absorption.

D. Route of administration (Table 1-1)

V. Distribution

• Distribution is the delivery of a drug from systemic circulation to tissues.

• Drugs may distribute into certain body compartments (Table 1-2).

A. Apparent volume of distribution (V_d)

1. Refers to the space in the body into which the drug appears to disseminate

2. It is calculated according to the following equation:

where C₀ = extrapolated concentration of drug in plasma at time 0 after equilibration (Fig. 1-4).

3. A large V_d means that a drug is concentrated in tissues.

TABLE 1-1 Routes of Administration

Route	Advantages	Disadvantages
Enteral
Oral	Most convenient Produces slow, uniform absorption Relatively safe Economical	Destruction of drug by enzymes or low pH (e.g., peptides, proteins, penicillins) Poor absorption of large and charged particles Drugs bind or complex with gastrointestinal contents (e.g., calcium binds to tetracycline) Cannot be used for drugs that irritate the intestine
Rectal	Limited first-pass metabolism Useful when oral route precluded	Absorption often irregular and incomplete May cause irritation to rectal mucosa
Sublingual/buccal	Rapid absorption Avoids first-pass metabolism	Absorption of only small amounts (e.g., nitroglycerin)
Parenteral
Intravenous	Most direct route Bypasses barriers to absorption (immediate effect) Suitable for large volumes Dosage easily adjusted	Increased risk of adverse effects from high concentration immediately after injection Not suitable for oily substances or suspensions
Intramuscular	Quickly and easily administered Possible rapid absorption May use as depot Suitable for oily substances and suspensions Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Like this: Like Loading... Related Related posts: Introduction to Autonomic and Neuromuscular Pharmacology Drugs Used in the Treatment of Parkinson’s Disease Other Cardiovascular Drugs Pharmacodynamics Stay updated, free articles. Join our Telegram channel Tags: Rapid Review Pharmacology Apr 8, 2017 \| Posted by admin in PHARMACY \| Comments Off on Pharmacokinetics Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access