Pharmacokinetics -- part 1 --

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Pharmacokinetics-- part 1 --

• W.M. Tom
• Department of Pharmacology
• University of Hong Kong

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Pharmacokinetics

• -- refers to the action of the body on the drug,
  including
• absorption
• distribution
• elimination -- metabolism excretion

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Drug Disposition
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Drug Absorption

• Peroral administration (P.O. route)
• swallowing
• commonly known as oral administration
• most convenient and economic method of systemic
  drug delivery
• dosage forms, e.g. tablets, capsules,
  syrups, etc.

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Drug absorption
Solids are not absorbed!
Dissolution is usually the rate limiting step!
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Drug Absorption

• Peroral administration (P.O. route)
• drug release ? formulation (e.g.
  tablets) e.g. particle size, surface area,
  excipients (inert substances)
• DISINTEGRATION (solid )
• ?
• DISSOLUTION (solution)
• ?
• ABSORPTION
• ?
• SYSTEMIC CIRCULATION ( bioavailability)

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Drug absorptionstomach (pH 13)in favour of
weak acid absorptionduodenum (pH 57)in
favour of weak base absorptionileum (pH
78)in favour of weak base absorption
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Diffusion Across Membrane
(pH lt pKa )
HA
Weak Acid
(pH gt pKa )
A-
(pH gt pKa )
B
Weak Base
(pH lt pKa )
BH
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Drug Absorption

• Factors affecting drug absorption by enteral
  routes
• 1. Drug dissolution
• -- depends on drug formulation of oral
  preparations
• 2. pH environment in GI tract
• -- unionized form efficiently absorbed
• 3. Lipid solubility of the drug
• -- nonpolar form easily absorbed

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Drug Absorption

• Factors affecting drug absorption by enteral
  routes
• 4. Effects of food
• -- in general delays drug absorption
• 5. First pass effect
• -- absorption of a drug into the portal
  circulation
• -- drug metabolized by liver before it reaches
  the systemic circulation

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First-pass effectmouthesophagusstomachsmal
l intestinecolonrectum
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First - Pass Effect
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Drug Absorption

• Parenteral routes
• 1. intravenous injection (IV)
• -- directly into a vein
• -- 100 bioavailability
• 2. intramuscular injection (IM) -- into a
  muscle
• -- depends on blood supply

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Drug Absorption

• Parenteral routes
• 3. subcutaneous injection (SC)
• -- under the skin
• -- intended for slow absorption
• 4. others -- inhalation
• -- sublingual
• -- topical
• -- transdermal, etc.

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Absorption, distribution, metabolism and
excretion
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Drug Distribution

• Drug transfer to various tissues
• -- depends on drug lipophilicity and blood flow
• Drug barriers
• -- e.g. blood-brain barrier, placenta
• Drug binding to plasma proteins
• -- bound drugs are pharmacologically inactive
• -- unbound drugs are free to distribute to
  target tissues
• -- different drugs may compete for binding to
  plasma proteins and displace each other from
  binding sites

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LOCUS OF ACTION RECEPTORS
TISSUE RESERVOIRS
Bound
Free
Free
Bound
ABSORPTION
Free Drug
EXCRETION
SYSTEMIC CIRCULATION
Bound Drug
BIOTRANSFORMATION
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Saturation of Protein Binding Sites

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Drug displacement from protein binding sites
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Plasma Protein Binding
consequence of drug displacement

• an increase in free drug concentration of the
  displaced drug ?? an increase in drug
  effect
• (be cautious when using a drug of low T.I.)
• a decrease in the duration of action of the
  displaced drug because more free drugs are
  available for elimination

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Drug Metabolism

• modification of the chemical structure by enzyme
  systems in the body
• -- e.g. cytochrome P450 in liver
• these chemical reactions produce water-soluble
  metabolites which are more readily excreted by
  the kidneys
• -- phase I reaction, e.g. oxidation
• -- phase II (conjugation) reaction, e.g.
  glucuronidation
• drug metabolism activity can be influenced by a
  variety of drugs

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The two phases of drug metabolism
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The two phases of drug metabolism
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Proportion of drugs metabolized by the major
phase I and phase II enzymes
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Drug Metabolism

• enzyme induction
• -- results in faster rate of metabolism
• -- e.g. in heavy cigarette smokers, alcoholics
• enzyme inhibition
• -- results in slower rate of metabolism
• -- e.g. taking another drug which uses the same
  enzyme for metabolism
• biological variations in drug metabolism
• -- e.g. genetics, disease states, age, etc.

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Drug Excretion

• in urine
• -- by glomerular filtration and renal tubular
  secretion -- polar water-soluble metabolites
  readily excreted while nonpolar forms
  reabsorbed back to circulation
• in bile and feces
• other routes
• -- e.g. in sweat, milk and other body fluids
• -- volatile gases by exhalation

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Renal excretion of drugs-- lipid-soluble
and un-ionized drugs are passively reabsorbed
through the nephron-- active secretion of
organic acids and bases occurs only in the
proximal tubular segment-- in distal tubular
segments, the secretion of H favours
reabsorption of weak acids (less ionized) and
excretion of weak bases (more ionized)
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Part 1 ended
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Pharmacokinetics-- part 2 --

• W.M. Tom
• Department of Pharmacology
• University of Hong Kong

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Time course of action of a single oral dose
Time of onset T1 - T0Time to peak
effect T2 - T0Duration of action T3 -
T1MEC minimum effective
concentration
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Time course of drug action

• time of onset
• -- the time taken for the drug to produce a
  response
• time to peak effect
• -- the time taken for the drug to reach its
  highest blood concentration
• duration of action
• -- the time during which the drug produces a
  response
• elimination half-life ( t 1/2 )
• -- the time taken to reduce the drug
  concentration in the blood by 50

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One Compartment IV Bolus Pharmacokinetic Model

• Assumptions
• drug is mixed instantaneously in blood
• drug in the blood is in rapid equilibrium with
  drug in the extravascular tissues
• drug elimination follows first order kinetics

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One Compartment IV Bolus Pharmacokinetic Model

• rate of concentration change at each time point
• dCp
• k Cp
• dt
• . (1)
• Cp plasma drug concnetration
• k elimination rate constant

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One Compartment IV Bolus Pharmacokinetic Model

• Ct C0 e k t .
  (2)
• Ct plasma concentration at time t
• C0 plasma concentration at time 0

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One Compartment IV Bolus Pharmacokinetic Model

• k t
• log Ct log C0 . (3)
• 2.303
• Ct plasma concentration at time t
• C0 plasma concentration at time 0

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One Compartment IV Bolus Pharmacokinetic Model

• Apparent volume of distribution (Vd )
• apparent volume that the drug is distributed into
• not a physiological volume
• amount of drug in the body X
• Vd
• drug conc. In plasma Cp
• DOSE
• or Vd . (4)
• C0

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One Compartment IV Bolus Pharmacokinetic Model

• DOSE
• Vd . (4)
• C0
• substitute (4) to (3), I.e. Ct C0 e k
  t
• DOSE
• Ct e k t . (5)
• Vd

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One Compartment IV Bolus Pharmacokinetic Model

• Half-Life of Elimination ( t 1/2 )
• time taken for the plasma concentration to fall
  to half its original value
• 0.693
• t 1/2 . (6)
• k

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One-compartment pharmacokinetics (single dose,
IV)Cp plasma drug concentration C0
plasma concentration at time zerok el
elimination constant elimination half-life
t 1/2 t 2 - t 1
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One Compartment IV Bolus Pharmacokinetic Model

• Drug clearance ( CL )
• a measure of he efficiency with which a drug is
  removed from the body
• rate of elimination amount of drug
  k
• CL
• Cp Cp
• Vd k . (7)
• CL total CL kidney CL liver CL others

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One Compartment IV Bolus Pharmacokinetic Model

• Bioavailability ( F )
• measures the extent of absorption of a given
  drug, usually expressed as fraction of the
  administered dose
• intravenous injection, by definition, has a
  bioavailability of 100
• AUC CL
• F .. (8)
• DOSE
• AUC area under the conc.-time curve

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Bioavailability
Plasma concentration
(AUC)o (AUC)iv
i.v. route
oral route
Time (hours)
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Multiple IV Bolus Dose Administration

• drug accumulation occurs when repeated doses are
  given before the drug is completely eliminated
• repeated drug administration at dose intervals (t
  ) will give a steady state with the plasma
  concentration fluctuating between a maximum
  (Cmax) and a minimum (Cmin ) value

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Plateau principle Css steady state
concentrationCmax maximum CssCmin
minimum CssMEC minimum effective
concentrationMTC minimum toxic
concentrationtherapeutic range MTC - MEC
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Time course of drug action

• plateau principle
• -- repeated drug administration at fixed dosage
  intervals will produce a plateau
  concentration of drug in the blood (I.e.
  steady state)
• steady state
• -- a state at which the rate of drug
  administration is equal to the rate of
  elimination
• therapeutic range
• -- the range between the minimum effective
  concentration (MEC) and the minimum toxic
  concentration (MTC) of a drug

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Effect of dosage intervals on drug concentration
curve 1 -- dosage interval too short
curve 2 -- too long curve 3 -- ideal
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Blood levels of drugs with intermittent dosage
a typical oral dosage four times a
day on a schedule of 10-2-6-10 or 9-1-5-9
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Time course of drug action

• loading dose
• -- a large dose given to achieve therapeutic
  concentration rapidly
• maintenance dose
• -- a dose given to maintain the drug
  concentration at steady state

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Combined Infusion and Bolus Administration

• to achieve a therapeutic concentration more
  quickly is to give a loading dose by rapid IV
  injection and then start the slower maintenance
  infusion
• Loading dose Css ? Vd
  ........... (9)
• Maintenance dose CL ? Cp ? ? . (10)

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Multi-compartment Pharmacokinetic Model

• the drug appears to distribute between 2 or more
  compartments
• the drug is not instantaneously equilibrated in
  various tissues
• rapidly perfused tissues often belong to the
  central compartment
• slowly perfused tissues belong to the peripheral
  compartment

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Two-compartment pharmacokinetics (single dose,
IV) central compartment (rapid)
t 1/2 ? peripheral compartment (slow)
t 1/2 ?
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Part 2 ended