Pharmacokinetics

Definition
-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)
 Measurement of drug concentration
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.
 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.

MTC

Therapeutic range
Intensity
MEC
Duration

Onset time

MEC=Minimum Effective Concentration

MTC=Maximum Toxic Concentration
Time to Peak Concentration

100
90
80
concentration

70
60 IV
50 Oral
40 Rectal
30
20
10
0
0 5 10 20 30 60 120 180
minutes
 Pharmacokinetic models
★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.
 Absorption (of drugs)
★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.

★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.
 Factors in drug absorption
★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

★Physicochemical considerations
1.pKa and degree of ionization
2.lipid solubility
3.dissolution of rate
Physiological considerations on drug absorption
〝 Cell membrance 〞
★Passive diffusion : ﹝ 高﹞ →﹝低﹞ , most drugs
--The movement of drug from a region of high to one low concentration
and no work required.
★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
Physiological considerations on drug absorption
〝 Cell membrance 〞
★Ion-paired transport :
--Highly ionized compounds: quaternary ammonium compound,
sulfonic acid.

★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.
Physiological considerations on drug absorption
〝 Gastric emptying 〞
■The transit of drug through stomach

■Therate of gastric emptying is a controlling step in the speed of

drug absorption.

★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 〞

dissolution absorption
Tablet, Capsule Drug in solution

disintegration dissolution
Granules, Aggregates
 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 Delayed Increased Not affected

Amoxicillin Acetaminophen Hydralazine Chlorpropamide

Ampicillin Cefaclor Hydrochlorothiazide Glibenclamide
Aspirin Cephalexin Metoprolol Glipizide
Isoniazid Digoxin Oxazepam Metronidazole
Levodopa Potassium ion Phenytoin Prednisone
Furosemide Sulfadiazine Propoxyphene
Penicillin G Sulfadimethoxine Propranolol
Tetracycline Sulfanilamide Theophylline
Rifampin Sulfasymazine
Doxycycline Sulfisoxazole
 Distribution (of drugs)
★Definition
-Distribution refers to the reversible transfer of drug from one location
to another within the body.

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 0.5
Less rapid perfused
Muscle 0.8 48.0
Skin 0.4 6.5
Poorly 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 drug
Activation 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
• Microsomal
 These 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
Drug Excretion
-most drugs are excreted in urine
either as unchanged or drug
metabolites

Renal Function
1. Glomerular filtration
2. Active tubular
secretion
3. Passive tubular
reabsorption
4. Excretion
 Excreted drug = (Filtered+ secreted) - reabsobed

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)
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-