Pharmacokinetics

Dr. SA Ziai

Pharmacokinetics examines the movement of a drug over time

through the body

Pharmacological as well as toxicological actions of drugs are primarily related to the plasma

concentrations of drugs

ADME

The speed of onset of drug action, the intensity of the drug’s effect, and the duration of drug action are controlled by four fundamental pathways of drug movement and modification in the body

Pharmacokinetic Principles

• In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route

• Drugs:– The active drug molecule– Prodrug– Absorbed into the blood from its site of administration – Distributed to its site of action– permeating through the various barriers that separate these

compartments– Eliminated at a reasonable rate by metabolic inactivation, by

excretion from the body, or by a combination of these processes

ROUTES OF DRUG ADMINISTRATION• Enteral

– Oral– Sublingual

• Parenteral– IV– IM– SC

• Other– Inhalation– Intranasal– Intrathecal/Intraventricular– Topical– Transdermal– Rectal

• Oral– Simple, Reversible– First-pass metabolism

• Sublingual

– Enteric coated • Parentral

– Heparin, Insulin– Unconscious patients– Rapid onset of action– Highest bioavailability (IV)– Irreversible, Pain, Infection – Rate of administration (IV)– Depot and suspension (IM)– Pumps, Implants (SC)

ABSORPTION OF DRUGS

Transport of a drug from the GI tract

• IV 100%• Passive diffusion

– Concentration gradient– Lipid soluble– Water soluble– Facilitated diffusion (by carrier)

• No energy, Saturated, Inhibited

• Active transport– ATP– Saturated– Moving against concentration gradient

• Endocytosis and exocytosis– Vit B12

Permeation

Aqueous Diffusion

• Across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000–30,000.

• Concentration gradient (Fick's law) • Bound to large plasma proteins (eg, albumin)• Electrical fields

BBB

• The capillaries of the brain, the testis• Drug export pumps (MDR pumps).

Lipid Diffusion

• The lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between aqueous and lipid media.

• In the case of weak acids and weak bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to move from aqueous to lipid or vice versa varies with the pH of the medium

• A weak acid is a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion).

• A weak base is a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton.

Effect of pH on drug absorption

• More of a weak acid will be in the lipid-soluble form at acid pH

• More of a basic drug will be in the lipid-soluble form at alkaline pH

The pKa is a measure of the strength of the interaction of a compound with a proton

The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug

Determination of how much drug will be found on either side

of a membrane

Trapping

Body Fluid Range of pH Total Fluid: Blood Concentration Ratios for Sulfadiazine (acid, pKa 6.5)

Total Fluid: Blood Concentration Ratios for Pyrimethamine (base, pKa 7.0)

Urine 5.0–8.0 0.12–4.65 72.24–0.79Breast milk 6.4–7.6

0.2–1.77 3.56–0.89

Jejunum, ileum contents 7.5–8.0

1.23–3.54 0.94–0.79

Stomach contents 1.92–2.59

0.11

85,993–18,386

Prostatic secretions 6.45–7.4

0.21 3.25–1.0

Vaginal secretions 3.4–4.2

0.114

2848–452

Body Fluids with Potential for Drug "Trapping" through the pH-Partitioning Phenomenon.

Special Carriers

• Peptides, amino acids, sugars• ABC (ATP-binding cassette) family – less selective– P-glycoprotein, multidrug-resistance type 1

(MDR1) transporter, multidrug resistance-associated protein (MRP)

– the solute carrier [SLC] family, do not bind ATP but use ion gradients for transport energy

Special CarriersTransporter Physiologic Function Pharmacologic SignificanceNET Norepinephrine reuptake from

synapseTarget of cocaine and some tricyclic antidepressants

SERT Serotonin reuptake from synapse

Target of selective serotonin reuptake inhibitors and some tricyclic antidepressants

VMAT Transport of dopamine and norepinephrine into adrenergic vesicles in nerve endings

Target of reserpine

MDR1 Transport of many xenobiotics out of cells

Increased expression confers resistance to certain anticancer drugs; inhibition increases blood levels of digoxin

MRP1 Leukotriene secretion Confers resistance to certain anticancer and antifungal drugs

Physical factors influencing absorption

• Blood flow to the absorption site– Blood flow to the intestine is much greater than the

flow to the stomach– Shock severely reduces blood flow to cutaneous

tissues• Total surface area available for absorption– Intestine has a surface rich in microvilli, it has a

surface area about 1000-fold that of the stomach• Contact time at the absorption surface– Diarrhea, Parasympathetic, Food

BIOAVAILABILITY• Determination• Factors that influence

– First-pass metabolism– Solubility of the drug– Chemical instability– Nature of the drug

formulation– Particle size, salt form, crystal

polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution

DRUG DISTRIBUTION

DRUG DISTRIBUTION

• Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.

• The delivery of a drug from the plasma to the interstitium primarily depends on:

• Blood flow• Capillary permeability • Protein binding• Hydrophobicity of the drug

Capillary permeability

VOLUME OF DISTRIBUTION

VOLUME OF DISTRIBUTION

• The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed.

• Water compartments in the body1. Plasma compartment (6%)

• Size and PB (Heparin)

2. Extracellular fluid (20%)• LMW and hydrophil Aminoglycosides

3. Total body water (60%)• Ethanol

4. Other sites• Fetus

Apparent volume of distribution

• A drug rarely associates exclusively with only one of the water compartments of the body. Instead, the vast majority of drugs distribute into several compartments, often avidly binding cellular components—for example, – lipids (abundant in adipocytes and cell membranes), – Proteins (abundant in plasma and within cells), or – Nucleic acids (abundant in the nuclei of cells).

• Therefore, the volume into which drugs distribute is called the apparent volume of distribution, or Vd

Effect of a large Vd on the half-life of a drug

• If the Vd for a drug is large, most of the drug is in the extraplasmic space and is unavailable to the excretory organs

• Therefore any factor that increases the volume of distribution can lead to an increase in the half-life and extend the duration of action of the drug

BINDING OF DRUGS TO PLASMA PROTEINS

Albumin has the strongest affinities for anionic drugs (weak acids)

and hydrophobic drugs

Competition for binding between drugs

DRUG METABOLISM

DRUG METABOLISM

• Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile.

• The process of metabolism transforms lipophilic drugs into more polar readily excretable products.

• The liver is the major site for drug metabolism

Reactions of drug metabolism

Phase I reactions utilizing the P450 system

• The Phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called microsomal mixed function oxidase):

Drug + O2 + NADPH + H+ → Drugmodified + H2O + NADP+

Electron flow in microsomal drug oxidizing system

CO

huCYP-Fe+2

Drug

CO

O2

e-

e-

2H+

H2O

Drug

CYPR-Ase

NADPH

NADP+

OHDrug

CYP Fe+3

PCDrug

CYP Fe+2

Drug

CYP Fe+2

Drug

O2

CYP Fe+3

OHDrug

Summary of the P450 system

• Metabolism of many endogenous compounds (steroids, lipids, etc.) and biotransformation of exogenous substances (xenobiotics).

• Cytochrome P450, designated as CYP• Composed of many families of heme-

containing isozymes

Summary of the P450 system

• There are many different genes, and many different enzymes

• Six isozymes are responsible for the vast majority of P450-catalyzed reactions: CYP3A4 (60%), CYP2D6 (25%), CYP2C9/10 (15%), CYP2C19 (15%), CYP2E1 (2%), and CYP1A2 (2%).

• An individual drug may be a substrate for more than one isozyme

• Considerable amounts of CYP3A4 are found in intestinal mucosa

Phase I reactions not involving the P450 system

• These include:– amine oxidation (for example, oxidation of

catecholamines or histamine)– alcohol dehydrogenation (for example, ethanol

oxidation)– esterases (for example, metabolism of pravastatin

in liver)– hydrolysis (for example, of procaine)

Phase II

• Conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are most often therapeutically inactive

• A notable exception is morphine-6-glucuronide, which is more potent than morphine

• Glucuronidation is the most common and the most important conjugation reaction

Phase II

• Neonates are deficient in this conjugating system, making them particularly vulnerable to drugs such as chloramphenicol

• Drugs already possessing an –OH, –HN2, or –COOH group may enter Phase II directly and become conjugated without prior Phase I metabolism

• The highly polar drug conjugates may then be excreted by the kidney or bile

Entero-hepatic Recirculation – clinical significanceOral contraceptive failure when an antibiotic is taken

An antibiotic such as rifampin also induces CYP enzymes that metabolize the contraceptive hormones and thus reduces their effectiveness even more

DRUG ELIMINATION

DRUG ELIMINATION

• The most important route is through the kidney into the urine.

• Other routes include the bile, intestine, lung, or milk in nursing mothers

Renal elimination of a drug• Glomerular filtration

– The glomerular filtration rate (125 mL/min) is normally about twenty percent of the renal plasma flow (600 mL/min)

– Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate

• Proximal tubular secretion– By two energy-requiring active transport

(carrier requiring) systems, one for anions and one for cations

– Premature infants and neonates have an incompletely developed tubular secretory mechanism

Renal elimination of a drug

• Distal tubular reabsorption–As a general rule, weak acids

can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.”

• For phenobarbital (weak acid) overdose we can give bicarbonate

• For cocaine, acidification of the urine with NH4Cl is useful

Quantitative aspects of renal drug elimination

• Plasma clearance is expressed as the volume of plasma from which all drug appears to be removed in a given time—for example, as mL/min

• Clearance equals the amount of renal plasma flow multiplied by the extraction ratio, and because these are normally invariant over time, clearance is constant

Total body clearance

• It is not possible to measure and sum these individual clearances. However, total clearance can be derived from the steady-state equation

Clinical situations resulting in changes in drug half-life

• The half-life of a drug is increased by 1. diminished renal plasma flow or hepatic blood flow—for

example, in cardiogenic shock, heart failure, or hemorrhage2. decreased extraction ratio—for example, as seen in renal

disease3. decreased metabolism—for example, when another drug

inhibits its biotransformation or in hepatic insufficiency, as with cirrhosis.

• The half-life of a drug may decrease by 1. increased hepatic blood flow2. decreased protein binding3. increased metabolism

Half-Life

• Half-life (t1/2) is the time required to change the amount of drug in the body by one-half during elimination (or during a constant infusion).

• Half-life is useful because it indicates the time required to attain 50% of steady state—or to decay 50% from steady-state conditions—after a change in the rate of drug administration.

Time required to reach the steady-state drug concentration