METABOLISM

• METABOLISM OF DRUG (BIOTRANSFORMATION)

 IS THE PROCESS OF CHEMICAL ALTERATION OF DRUGS IN THE BODY

 PRINCIPLES
1. THE LIVER IS THE MAJOR SITE OF METABOLISM FOR MANY DRUGS OR OTHER XENOBIOTICS.
OTHERS ORGANS: LUNGS, KIDNEYS AND ADRENAL GLANDS
2. MANY LIPID-SOLUBLE, WEAK ORGANIC ACIDS OR BASES ARE NOT READILY ELIMINATED FROM
BODY AND MUST BE CONJUGATED OR METABOLIZED TO COMPOUNDS THAT ARE MORE POLAR
AND LESS LIPID-SOLUBLE BEFORE BEING EXCRETED.
3. METABOLISM OFTEN RESULTS IN INACTIVATION OF THE COMPOUND.
4. SOME DRUGS ARE ACTIVATED BY METABOLISM. THESE SUBSTANCES ARE CALLED PRODRUGS.
 BIOACTIVATION

• PARENT DRUG IS INACTIVE AND THE

METABOLITE IS ACTIVE OR HAS
PHARMACOLOGICAL ACTIVITY
FACTORS AFFECTING DRUG METABOLISM
GENETICS- SEVERAL DRUG METABOLIZING SYSTEMS
HAVE LONG BEEN KNOWN TO DIFFER AMONG
FAMILIES OR POPULATIONS IN GENETICALLY
DETERMINED WAYS.
CHEMICAL PROPERTIES OF THE DRUG-
COADMINISTRATION OF CERTAIN AGENTS MAY ALTER
THE DISPOSITION OF MANY DRUGS.
 FACTORS AFFECTING DRUG METABOLISM
ROUTE OF ADMINISTRATION- E.G. ORAL ROUTE CAN RESULT IN HEPATIC
METABOLISM OF SOME DRUGS (FIRST-PASS EFFECT).
DIET- STARVATION CAN DEPLETE GLYCINE STORES AND ALTER GLYCINE
CONJUGATION
DOSAGE- TOXIC DOSES CAN DEPLETE ENZYMES NEEDED FOR DETOXIFICATION
REACTIONS.
AGE AND GENDER- YOUNG MALES ARE MORE PRONE TO SEDATION FROM
BARBITURATES THAN FEMALES
DISEASE
CIRCADIAN RHYTHM
ELIMINATION
 ALONG WITH THE DOSAGE, THE RATE OF
ELIMINATION FOLLOWING THE LAST DOSE
(DISAPPEARANCE OF THE ACTIVE MOLECULES
FROM THE BLOODSTREAM OR BODY) DETERMINES
THE DURATION OF ACTION OF MOST DRUGS
A. FIRST ORDER ELIMINATION

 IMPLIES THAT THE RATE OF ELIMINATION IS PROPORTIONAL TO THE

CONCENTRATION (THE HIGHER THE CONCENTRATION, THE GREATER THE
DRUG ELIMINATED PER UNIT TIME).
GIVE 100 MG OF A DRUG
1 HALF-LIFE …………..50
2 HALF-LIVES………… 25
3 HALF-LIVES …….….12.5
4 HALF-LIVES …………6.25
5 HALFLIVES …………3.125
6 HALF-LIVES …………1.56

5 HALF-LIVES = 97% OF DRUG

ELIMINATED
B. ZERO-ORDER ELIMINATION

 IMPLIES THAT THE RATE OF ELIMINATION IS

CONSTANT REGARDLESS OF CONCENTRATION
 BLOOD CONCENTRATION OF DRUG IS REDUCED
IN EQUAL AMOUNT OR ELIMINATED IN
CONTINUANT SHORTEN HALF-LIFE (T1/2 ).

 CONCENTRATION OF DRUGS IN PLASMA

DECREASE IN LINEAR FASHION OVER TIME
 E.G. ETHANOL, ASPIRIN, PHENYTOIN
C. NON-LINEAR KINETICS
LOW DOSE→ 1ST ORDER
OVERDOSE→ ZERO ORDER

ASPIRIN-
LOW DOSE→ FIRST
ORDER→T1/2=2-3 H
LARGE DOSE→URINE PH↓ →
REABSORPTION ↑ → ZERO
ORDER →T1/2=15-30 H
CLEARANCE (CL)
 RELATES THE RATE OF ELIMINATION TO PLASMA
CONCENTRATION:
CLEARANCE= RATE OF ELIMINATION OF DRUG
PLASMA DRUG CONCENTRATION
(UNITS= VOLUME PER UNIT TIME)
HALF-LIFE OF DRUG (T ) 1/2

THE HALF-LIFE (T ) IS THE TIME REQUIRED TO

1/2

DECREASE THE DRUG PLASMA CONCENTRATION BY ONE-HALF (50%) DURING

ELIMINATION.

T = ELIMINATION HALF LIFE

1/2

V = VOLUME OF DISTRIBUTION
D

CL = ELIMINATION CLEARANCE
E
 C

GIVE 100 MG OF A DRUG

1 HALF-LIFE …………..50 one compartment
2 HALF-LIVES………… 25
3 HALF-LIVES …….….12.5
4 HALF-LIVES …………6.25
5 HALF-LIVES …………3.125
6 HALF-LIVES …………1.56

5 HALF-LIVES = 97% OF DRUG T

ELIMINATED
t1/2
• STEADY-STATE CONCENTRATION (CSS)

• CONDITION IN WHICH THE AVERAGE TOTAL AMOUNT OF DRUG IN THE BODY DOES NOT CHANGE
OVER MULTIPLE DOSING INTERVALS

• RATE OF DRUG ADMINISTRATION EQUALS THE RATE OF ELIMINATION

• REACHED IN 4-5 HALF LIVES OF THE DRUG

• LOADING DOSE
• IT IS A FIRST DOSING AMOUNT THAT ACHIEVES CSS
RAPIDLY, BEFORE GIVEN ROUTINE DOSE

• LOADING DOSE=AMOUNT IN THE BODY ACHIEVING

CSS IMMEDIATELY FOLLOWING THE LOADING DOSE

• LOADING DOSE IS A BEGINNING DOSE THAT

PROMPTLY RAISES THE CONCENTRATION OF DRUG IN
PLASMA TO THE TARGET CONCENTRATION
• THERAPEUTIC WINDOW
• USEFUL RANGE OF CONCENTRATION OVER WHICH A DRUG IS
THERAPEUTICALLY BENEFICIAL. THERAPEUTIC WINDOW MAY
VARY FROM PATIENT TO PATIENT

• DRUGS WITH NARROW THERAPEUTIC WINDOWS REQUIRE

SMALLER AND MORE FREQUENT DOSES OR A DIFFERENT
METHOD OF ADMINISTRATION

• DRUGS WITH SLOW ELIMINATION RATES MAY RAPIDLY

ACCUMULATE TO TOXIC LEVELS….CAN CHOOSE TO GIVE ONE
LARGE INITIAL DOSE, FOLLOWING ONLY WITH SMALL DOSES
 THE ENTEROHEPATIC SHUNT

Drug Liver

Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide produced
beta glucuronidase
gall bladder

Portal circulation

Gut
DRUG EVALUATION AND
REGULATION
THANK YOU!
• FDA RATINGS OF DRUG SAFETY IN PREGNANCY

•CATEGORY A
•ADEQUATE AND WELL-CONTROLLED STUDIES HAVE FAILED TO DEMONSTRATE A RISK TO THE
FETUS IN THE FIRST TRIMESTER OF PREGNANCY (AND THERE IS NO EVIDENCE OF RISK IN
LATER TRIMESTERS).

•CATEGORY B
•ANIMAL REPRODUCTION STUDIES HAVE FAILED TO DEMONSTRATE A RISK TO THE FETUS AND
THERE ARE NO ADEQUATE AND WELL-CONTROLLED STUDIES IN PREGNANT WOMEN.

•CATEGORY C
•ANIMAL REPRODUCTION STUDIES HAVE SHOWN AN ADVERSE EFFECT ON THE FETUS
AND THERE ARE NO ADEQUATE AND WELL-CONTROLLED STUDIES IN HUMANS, BUT
POTENTIAL BENEFITS MAY WARRANT USE OF THE DRUG IN PREGNANT WOMEN DESPITE
POTENTIAL RISKS.
• CATEGORY D
• THERE IS POSITIVE EVIDENCE OF HUMAN FETAL RISK BASED ON
ADVERSE REACTION DATA FROM INVESTIGATIONAL OR MARKETING
EXPERIENCE OR STUDIES IN HUMANS, BUT POTENTIAL BENEFITS MAY
WARRANT USE OF THE DRUG IN PREGNANT WOMEN DESPITE
POTENTIAL RISKS.

• CATEGORY X
• STUDIES IN ANIMALS OR HUMANS HAVE DEMONSTRATED FETAL
ABNORMALITIES AND/OR THERE IS POSITIVE EVIDENCE OF HUMAN
FETAL RISK BASED ON ADVERSE REACTION DATA FROM
INVESTIGATIONAL OR MARKETING EXPERIENCE, AND THE RISKS
INVOLVED IN USE OF THE DRUG IN PREGNANT WOMEN CLEARLY
OUTWEIGH POTENTIAL BENEFITS.