8/22/2013

PHARMACOKINETICS – II OUTLINE
Metabolism & Excretion
A. DRUG METABOLISM
I. Phase I and II reactions
II. CYP- 450 enzyme system
Dr Ruwan Parakramawansha III. First- pass metabolism
MBBS, MD, MRCP(UK),MRCPE, DMT(UK)
(2013/08/22)

B. EXCRETION OF DRUGS
I. Renal excretion
II. Biliary excretion

DRUG ELIMINATION
DRUG METABOLISM

....is the irreversible loss of drug from the body. It occurs by two
The lipophilic nature of drugs promote passage
processes: metabolism and excretion through biological membranes and thereby,
a. allow subsequent access to their sites of action

Humans have evolved complex systems that detoxify foreign
chemicals (xenobiotics), including carcinogens and toxins giving therapeutic effects
present in their diet b. hinder their excretion from the body

The ability of humans to metabolize and clear drugs is a natural

process that involves the same enzymatic pathways and

∴ metabolism of drugs into more hydrophilic
transport systems that are used for normal metabolism of metabolites is essential for their elimination from the
dietary constituents body, as well as for termination of their biological
and pharmacological activity

DRUG METABOLISM DRUG METABOLISM

In general, biotransformation reactions generate
Classified into two types:
more polar, inactive metabolites that are readily 1. Phase I (functionalization)) reactions
excreted from the body .......introduce or expose a functional group on
the parent compound

Exceptions include prodrugs that are converted into
more active substances after metabolism
2. Phase II (biosynthetic / conjugation)
e.g. enalapril reactions
... involve conjugation of a reactive group
(often inserted during phase I reaction)

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DRUG METABOLISM

Phase I reactions - result in the biological

inactivation of the drug

Phase II reactions - produce a metabolite

with improved water solubility, facilitating the
excretion of the drug from the body

SITE OF DRUG METABOLISM

Metabolizing enzymes are located in

1. Liver
2. Small and large intestines
3. Lungs

Phase I enzyme systems - in the
endoplasmic reticulum

Phase II enzyme systems - mainly cytosolic

PHASE 1 REACTIONS PHASE 1 REACTIONS

Phase I enzymes either adds or exposes a
Phase I oxidation reactions are carried out by,
functional group, permitting the products of
phase I metabolism to serve as substrates
for the phase II conjugating or synthetic 1. Cytochrome P-450 Superfamily (CYPs))
enzymes 2. Flavin-containing monooxygenases

Phase I reactions involve oxidation, reduction
and hydrolysis. 3. Epoxide hydrolases

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THE CYTOCHROME P-450 THE CYTOCHROME P-450

SUPERFAMILY SUPERFAMILY

The CYPs are a superfamily of enzymes, all of which
Based on amino acid sequence similarities in the
contain a molecule of haeme that is non-covalently genes grouped into a superfamily composed of
bound to the polypeptide chain families and subfamilies

CYP3A4

More than 50 individual CYPs have been identified in Family Subfamily Gene number
humans.

THE CYTOCHROME P-450 THE CYTOCHROME P-450

SUPERFAMILY SUPERFAMILY

In humans, three main CYP families (CYP1, CYP2
CYPs have the capacity to metabolize
and CYP3) are involved in drug metabolism diverse chemicals due to

CYP3A4 is involved in the metabolism of over 50% a. multiple forms of CYPs
of clinically used drugs
b. the capacity of a single CYP to metabolize many
structurally distinct chemicals

CYPs - mainly located in liver c. a single compound can also be metabolized by
- throughout the GI tract different CYPs
- in lower amounts in lung, kidney and CNS
This property is due to large and fluid
substrate binding sites in the CYP

THE CYTOCHROME P-450 CYPS AND DRUG-DRUG

SUPERFAMILY INTERACTIONS

Overlapping substrate specificity of CYPs
Drug- drug interactions commonly inhibit the
lead to.... drug metabolism by CYPs but sometimes
induces the enzyme action
i. Slower metabolic rate
The most common mechanism of enzyme
ii. drug-drug interactions induction is transcriptional activation leading
to increased synthesis of more CYP enzyme
proteins

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CYPS AND DRUG-DRUG CYPS AND DRUG-DRUG

INTERACTIONS INTERACTIONS

Mechanisms of CYP inhibition:
Drug- drug interactions commonly occur

a. When two drugs metabolised by the same CYP when two drugs are co-administered and
enzyme – competitive inhibition
subjected to metabolism by the same
e.g. Simvastatin and Erythromycin
enzyme
b. Some drugs compete for the active site but are not
themselves substrates – competitive inhibition
e.g. Quinidine inhibitor of CYP2D6
Thus, it is important to determine the identity
c. Independently of being substrates for a CYP – of the CYP that metabolizes a particular drug
non-competitive inhibition
and to avoid co-administering drugs that are
e.g. Ketoconazole- by forming a tight complex with the
haem moiety of CYP3A4 metabolized by the same enzyme

CLINICALLY IMPORTANT CYP

INHIBITORS & INDUCERS

CYP INHIBITORS CYP INDUCERS

CIMETIDINE BARBITURATES

SOME MACROLIDES CARBAMAZEPINE

SOME ANIFUNGALS PHENYTOIN

SOME 4-QUINOLONES RIFAMPICIN

SOME HIV AGENTS ETHANOL (CYP2E1)

GRAPEFRUIT JUICE CIGARETTE SMOKE

Flavin-Containing
Monooxygenases (FMOs) PHASE II REACTIONS

Another superfamily of phase I enzymes
Involve conjugation of a reactive group and usually
involved in drug metabolism lead to inactive and polar products that are readily
excreted

Similar to CYPs, the FMOs are expressed at
high levels in the liver and are bound to the

However morphine and minoxidil, glucuronide and
endoplasmic reticulum sulfate conjugates, respectively, are more

Minor contributors to drug metabolism pharmacologically active than the parent

In contrast to CYPs,FMOs are not induced or
easily inhibited ⇒ not involved in drug-drug
interactions

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PHASE II REACTIONS PHASE II REACTIONS

Include several superfamilies of conjugating
The catalytic rates of phase 2 reactions are
enzymes. significantly faster than the rates of the CYPs
e.g. Glutathione-S-transferases

UDP-glucuronosyltransferases
The rate limiting step of drug metabolism is
Sulfotransferases
the initial (phase I) oxidation reaction
N-acetyltransferases

Methyltransferases

N-ACETYLATION

Following the discovery of isoniazid 5-15% of

patients on isoniazid experienced toxicities
that ranged from numbness and tingling in
their fingers to CNS damage

Elimination of isoniazid depends mainly on
acetylation, catalysed by an acetyltransferase
enzyme
Distribution of individual plasma concentrations for two drugs in humans.
[A] Aspirin [B] Isoniazid

N-ACETYLATION FIRST-PASS METABOLISM

Metabolic inactivation of a significant

Pharmacogenetic studies led to the proportion of an orally administered drug
classification of "rapid" and "slow" acetylators, before the drug reaches the systemic
with the "slow" phenotype being predisposed circulation
to toxicity

This occurs either the intestinal epithelium or
the liver

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FIRST-PASS METABOLISM FIRST-PASS METABOLISM

DRUGS THAT UNDERGO SUBSTANTIAL FIRST-PASS METABOLISM

First-pass metabolism significantly limits the
oral bioavailability of highly metabolized Aspirin
drugs Metoprolol

As a result a much larger dose of the drug is Glyceryl trinitrate
needed when it is given orally than when it is Morphine
given parenterally Propranolol
Levodopa
Salbutamol
Verapamil

EXCRETION OF DRUGS RENAL EXCRETION

Excretory organs except lungs eliminate
polar compounds more efficiently than
Involves three distinct processes:
substances with high lipid solubility

Routes of excretion 1. Glomerular filtration
– Renal
– Gastrointestinal 2. Active tubular secretion
– Lungs
– Breast milk 3. Passive tubular reabsorption

GLOMERULAR FILTRATION TUBULAR SECRETION

The amount of drug entering the tubular
∼ 80% of the drug delivered to the kidney is presented
lumen by filtration depends on.. to the PCT via peritubular capillaries
1. Glomerular filtration rate
2. Extent of plasma binding of the drug
Tubular secretion is potentially the most
effective mechanism of renal drug elimination

Up to 20% of renal plasma flow is filtered
through the glomerulus

Occurs via carrier-mediated membrane transporters
against a concentration gradiant

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TUBULAR SECRETION TUBULAR SECRETION

Unlike glomerular filtration, carrier-mediated
Many drugs compete for the same transport
transport can achieve maximal drug system ⇒ drug interactions
clearance even when most of the drug is
bound to plasma proteins e.g. Probenecid - prolong the action of penicillin by
e.g. Penicillin retarding its tubular secretion
(although ∼ 80% protein bound and therefore
cleared only slowly by filtration, almost completely
removed by proximal tubular secretion)

TUBULAR REABSORPTION TUBULAR REABSORPTION

∼99% water in the glomerular filtrate is
Lipid-soluble drugs are therefore excreted poorly,
reabsorbed as fluid traverses the tubule whereas polar drugs of low tubular permeability
remain in the lumen and become progressively
concentrated as water is reabsorbed

Create a concentration gradient for drug e.g. digoxin and aminoglycoside antibiotics
molecules

The degree of ionization of many drugs-weak acids
or weak bases-is pH dependent, and this markedly

If lipid soluable the drug will be reabsorbed influences their renal excretion
passively down concentration gradient

RENAL EXCRETION RENAL CLEARANCE

For drugs not inactivated by metabolism, the rate of
Elimination of drugs by the kidneys is best
renal elimination is the main factor that determines quantified by the renal clearance (CLr)
their duration of action
e.g. Frusemide, gentamicin, digoxin, methotrexate

Defined as the volume of plasma containing

These drugs have to be used with special care in the amount of substance that is removed
individuals whose renal function may be impaired, from the body by the kidneys in unit time
including the elderly and patients with renal disease

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RENAL CLEARANCE BILIARY EXCRETION

Transporters present in the canalicular membrane of

the hepatocyte actively secrete drugs and
CLr = Cu × Vu metabolites into bile
Cp e.g. Vecuronium , Rifampicin

Drugs and metabolites present in bile are released

Cp - plasma concentration into the GI tract during the digestive process
Cu - urinary concentration
Vu - rate of flow of urine

ENTEROHEPATIC RECYCLING SUMMARY

Drugs and metabolites being reabsorbed back into

the body from the intestine (in the case of
A. DRUG METABOLISM
conjugated metabolites, require their enzymatic I. Phase I and II reactions
hydrolysis by the intestinal microflora) II. CYP- 450 enzyme system
III. First- pass metabolism

Create a 'reservoir' of recirculating drug that can
amount to about 20% of total drug in the body and
prolongs drug action B. EXCRETION OF DRUGS
e.g. Morphine, ethinylestradiol I. Renal excretion
II. Biliary excretion

Thank you !