PharmacokineticsDefinition -Pharmacokinetics (in Greek: 〝 pharmacon 〞 meaning drug and 〝 kinetikos 〞 meaning putting in motion , the study of time dependency) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism.

-Pharmacokinetics is the study and characterization of the time course of drug absorption, distribution, metabolism and excretion. This sometimes is referred to as the ADME scheme.

- Pharmacokinetics also concerns the relationship of the processes to the intensity and time course of therapeutic and toxicologic effects of drugs.

Pharmacokinetics (ADME)

1.Sampling of biological speciments --Invasive methods: Blood, spinal fluid, tissue biopsy.

--Non-invasive methods: Urine, salive, feces, expired air

★Measurement of drug concentration in the blood, serum or plasma is the most direct approach to assess the pharmacokinetics of drug in body.

2.Significance of measuring plasma drug concentration★The intensity of the pharmacologic or toxic effect of a drug is often related to the concentration of the drug at the receptor sites.

★Monitoring the concentration of drugs in the blood or plasma ascertains that the calculated dose actually delivers the plasma level required for therapeutic effect.

Measurement of drug concentration

Plasma level-time curve★The plasma level-time curve is generated by measuring the drug concentration in plasma samples taken at various time intervals after a drug product is administered.

MEC

Duration

Onset time

Intensity

MTC

Therapeutic range

MEC=Minimum Effective ConcentrationMTC=Maximum Toxic Concentration

Time to Peak Concentration

0102030405060708090

100

0 5 10 20 30 60 120 180

minutes

con

cent

rati

on

IVOralRectal

★Drugs are in a dynamic state with the body.

★Various mathematical models can be devised to stimulate the rate processes of drug absorption, distribution and elimination. These mathematical models make possible the development of equations to describe drug concentrations in the body as a function of time.

★Pharmacokinetic models are useful to:

1.predict plasma, tissue and urine drug levels with dosage regimen.

2.calculate the optimum dosage regimen for each patient individually.

3.estimate the possible accumulation of drug and/or metabolites.

4.correlate drug concentration with pharmacologic or toxiciologic

activity.

5.evaluate differences in the rate or extent of availability between

formulations.

6.describe how changes in physiology or disease affect the absorption.

7.explain drug interactions.

Pharmacokinetic models

★Definition -The process of uptake of the compound from the site of administration into the systemic circulation.

-The rate of absorption will determine how soon the effects of the drug will begin.

-The extent of absorption will determine how intense the effects will be.

Absorption (of drugs)

★At the site of absorption, the systemic absorption of a drug is dependent upon:

1.the anatomy and physiological functions

2.the physicochemical properties of the drugs

3.the nature of the drug product.

★Physiological considerations

1.movement of drug across the membrane

2.blood flow: a potential rate limiting step

3.gastric emptying

4.pH of GI tract

Factors in drug absorption

★Physicochemical considerations

1.pKa and degree of ionization

2.lipid solubility

3.dissolution of rate

★Passive diffusion : ﹝高 →﹞ ﹝低﹞ , most drugs

--The movement of drug from a region of high to one low concentration

and no work required.

Physiological considerations on drug absorption

〝 Cell membrance 〞

★Active diffusion : ﹝低 →﹞ ﹝高﹞ , 如： Vitamin C

--Carrier --Specificity

--Saturation of transport --Competitive inhibition

--against concentration gradient --ATP needed

★Facilitated diffusion : ﹝高 →﹞ ﹝低﹞ , 如： Vitamin B12

--Carrier --Specificity

--Saturation of transport --Competitive inhibition

--With concentration gradient --Not ATP needed

★Ion-paired transport : --Highly ionized compounds: quaternary ammonium compound, sulfonic acid.

Physiological considerations on drug absorption

〝 Cell membrance 〞

★Pinocytosis : --The absorption of small fat, oil droplets, solid particle, starch, vitamin A, D, E, K.

★Pore transport : --Very small molecules (urea, water, sugar) are able to rapidly cross cell membranes as the membrane contained pores.

■The transit of drug through stomach

■The rate of gastric emptying is a controlling step in the speed of drug absorption.

Physiological considerations on drug absorption

〝 Gastric emptying 〞

★Retard gastric emptying:

--Fatty acid in diet, high concentration of electrolyte or hydrogen ion,

high viscosity or bulk mental depression, lying on the left side,

gastroenteritis, gastriculcer, hypothyroidism

--Drug: desipramine, chlorpromazine (Morefine®), Al(OH)3

★Retard gastric emptying:

--Fasting, hunger, alkali buffer solution, anxiety, lying on the right side,

hyperthyroidism

--Drug: metoclopramide (Primperan®)

Physicochemical considerations on drug absorption

〝 Dissolution rate 〞

Tablet, Capsuledissolution

Drug in solutionabsorption

disintegration

Granules, Aggregates

dissolution

Factors affecting the dissolution rate

★The effective surface area of the drug:

--Particle size: the smaller the drug particles, the greater of surface

area for a given amount of drug, especially for a

hydrophobic drug. (ex: aspirin, digoxin, phenobarbital)

-- Manufacturing process: such as lubricant, disintegrating agent and

compression force.

★The saturation solubility of the drug:

--Salt form : the dissolution rate of a salt form of a drug should be great

than the rate of the non-ionized form of the drug .

-- pH effect: as pH increased, the dissolution rate of W.A. is increased;

as pH increased, the dissolution rate of W.B. is increased.

-- Solvate form: drug can associate with solvent to produce crystalline

form called solvate. (ex: caffeine, theophylline, ampicillin)

Factors affecting the dissolution rate

★The influence of food:

--GI tract content↑: gastric emptying↓, dissolution rate↓

--High protein content: secretion of bile salt and blood flow ↑ ,

dissolution rate↑

★The effect of food:

--Fatty food: delay stomach emptying time beyond 2 hrs.

--Fluid: distend stomach and speed up stomach emptying.

--Full glass of water: sufficient water is necessary for dissolution of

the drug.

Drugs whose absorption is reduced, delayed, increased, or not affected by the

presence of food.

Reduced

Amoxicillin

Ampicillin

Aspirin

Isoniazid

Levodopa

Furosemide

Penicillin G

Tetracycline

Rifampin

Doxycycline

Delayed

Acetaminophen

Cefaclor

Cephalexin

Digoxin

Potassium ion

Sulfadiazine

Sulfadimethoxine

Sulfanilamide

Sulfasymazine

Sulfisoxazole

Increased

Hydralazine

Hydrochlorothiazide

Metoprolol

Oxazepam

Phenytoin

Propoxyphene

Propranolol

Theophylline

Not affected

Chlorpropamide

Glibenclamide

Glipizide

Metronidazole

Prednisone

★Definition

-Distribution refers to the reversible transfer of drug from one location

to another within the body.

Distribution (of drugs)

Factors influence the distribution of drugs

1.Blood circulation and vascular permeability: to achive site of action

2.Plasma protein binding: bound drug do not cross membranes

3.Lipophilicity of drug: lipophilic drugs accumulate in adipose tissue

4.Volume of distribution: a hypothetical volume of body that would be

required to dissolve the total amount of drug at the same

concentration as that found in the blood.

Blood circulation and vascular permeability

Tissue Blood flow (L/min) Tissue mass (% of B.W.)

Blood 5.4 8.0

Rapid perfused Brain 0.75 2.0 Liver 1.55 3.5 Kidney 1.2 0.5 Heart 0.25 0.5Less rapid perfused Muscle 0.8 48.0 Skin 0.4 6.5Poorly perfused Fat 0.25 14.0 Skeleton 0.2 17.0

Plasma protein binding Plasma protein normal range of drug bound concentration (g/L)

Albumin 35-50 acidic drug α-acid glycoprotein 0.4-1.0 basic drug Lipoprotein variable variable

Factors influence the plasma protein concentration

1. Protein synthesis: liver disease

2. Protein catabolism: trauma, surgery

3. Distribution of albumin between intra- and extravascular space:

(ex: burn: extravascular space)

4. Excessive elimination of plasma protein, particularly albumin:

(ex: renal disease)

Consequences of drug protein binding

1. Insoluble drugs and endogenous chemicals are carried in the blood in

the bound form. (ex: lipophilic steroid, vitamin)

2. Can increase the absorption rate of drug, especially ionized drug

remained in GI tract.

3. Lead to an even distribution throughout the body tissue.

4. Serve a storage function

5. Only the unbound drug is available for biotransformation or excretion

and a high degree of binding can result in delayed elimination.

6. Change in the binding of highly bound drugs can result in significant

change in clinical response or cause a toxic response.

Metabolism (of drugs) Definition -Biotransformation means chemical alteration of the drug in the body.

-The majority of metabolism leads to conversion of relatively lipid- soluble drugs into relatively water-soluble forms which are easily excreted in the kidney.

-Most hydrophilic drugs e.g. neostigmine, decamethonium are not biotranformed.

-Liver is the primary route of drug metabolism.

Biotransformation of drug may

Inactivation of drug Active metabolite from an active drugActivation of inactive drugs

Phase I Reaction/Nonsynthetic

reaction Oxidative reaction: Barbiturates,

Phenothiazine

Redcutive reaction: Halothane, Chloral hydrates

Hydrolytic reaction: Oxytocin, Pethidne Cyclization: Proguanil Decyclization: Phenytoin

Phase II/synthetic reaction

• Glucuronide conjugation: Oral contraceptive

• Acetylation: Sulphonamides

• Methylation: Adrenaline

• Sulphate conjugation: adrenal and sex steriods

• Glycine conjugation: Salicylates

• Glutathione conjugation: paracetamol

• Ribonucleoside/nucleotide synthesis: alcohol

Other

• MicrosomalThese are located in the smooth

endoplasmic reticulum, primarily in the liver

• Nonmicrosomal These are present in the cytoplasm and

mitochondria of hepatic cell.

Drug changes to active metabolite

Imipramine (Tofranil®) Despramine

Propranolol ( Inderal®) 4-hydroxypropranolol

Lidocaine (Xylocainel®) monoethylglycinexylidide

Drug changes to hazardous metabolite

Acetaminophen (Scanol®) N-acetyl-p-benzoquinoneimine hepatitis

Isoniazid (INH®) acetylhydrazine hepatitis

Drug changes to active drug

Enalapril (Sintec® , Enalatec® ) Enalaprilat

Renal Function1. Glomerular filtration2. Active tubular

secretion3. Passive tubular

reabsorption4. Excretion

Drug Excretion-most drugs are excreted in urine either as unchanged or drug metabolites

Glomerular Filtration- 1st step in renal drug excretion

Drug enters renal tubule as a dissolved solute

Drug filtration rate= Free drug Plasma conc. X Glomerular filtration rate (GFR)

Excreted drug = (Filtered+ secreted) - reabsobed

Active Tubular Secretion-some drugs especially weak acids and bases undergo active tubular secretion by transport systems located in the proximal tubular cells

Not affected by plasma protein binding as free drug is transported bound drug dissociates to replace free drug that has been transported.

Passive Reabsorption-most substances are reabsorbed across renal tubular cells if unionized and lipid soluble

Other routes of excretion:

Biliary excretion- drugs with mwts >300 excreted in to bile

Enterohepatic cycling-