Transcript Pharmacokinetics

2004-2005
Module 2
#2
Pharmacokinetics
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absorption of drugs
• drugs can be given iv, im, sc, orally (po)
• if given parenterally, they should be water
soluble
oral absorption is more complex:
tablet----dissolves in gut water----lipid soluble form
crosses gut barrier-----must escape liver (first pass
metabolism)
amount absorbed is bioavailability
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Which definition is correct?
• “Drug absorption refers to the passage of a
drug from its site of administration into the
circulation” –Brenner
• “Absorption describes the rate and extent to
which a drug leaves its site of
administration and reaches its site of action”
–Goodman & Gilman
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Pharmacokinetics
(how the body handles drugs)
(a,d,m,e)
most drugs are weak acids or bases:
HA
BH+
H+ + AB + H+
pH=pKa + log (base)
(acid)
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when H increases get more
HA and BH+
only the non-ionized form can
cross cell membranes
even if the drug is not ionized, it
still needs to be lipid soluble to
cross cell membranes
distribution of drugs
once in the body, drugs distribute to tissues
the ratio:
amount in the body/plasma concentration is
Volume of distribution (Vd)
some drugs assume these:
TBW
= 0.6 L/Kg (42 l) Ethanol 0.54 l/kg
ECF vol
= 0.2 L/Kg (12 l) Gentamicin 0.31 l/kg
Plasma vol. = 0.05 L/Kg (3 l) warfarin 0.14 l/kg
Blood vol
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= 5.5 l
volume of distribution
Cp0
Vd = Dose (mg)/Cp0 (mg/L)= Litres
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volume of distribution-2
• sometimes the Vd is anatomically “correct”
(e.g. ethanol, gentamicin, warfarin)
• sometimes it’s not: (e.g.. THC 9L/Kg,
amiodarone 66 L/Kg –highly lipd soluble lipid:plasma ratio
>300:1)
drugs with low Vd are often bound to plasma proteins
drugs with high Vd are often bound to tissue
components (proteins or fat)
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Clarifying Vd
• Vd is the ratio of the amount of drug in the body at any
time (t) to the plasma concentration (Cp) at that time.
• The only time we can be absolutely sure of the amount of
drug in the body is at time 0. This is the dose of the drug
that we gave iv.
• We can’t measure directly the Cp0, but we can extrapolate
it from later points in the log Cp vs. time curve.
• When we calculate Vd, we sometimes get an unrealistic
number.
• We normalize Vd to Litres/Kg of body weight. If the Vd
ethanol is 48 litres and the body weigh 80 Kg: the Vd
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ethanol is 0.6 L/Kg
filtration
excretion
reabsorption
secretion
• filtration
free drug only, not protein bound
• reabsorption
passive, lipid soluble form only (pH)
• secretion
active, acids and bases, saturable
Plasma pH is constant; urine pH varies from 5.0-8.0
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excretion-2
if the drug is water soluble, the kidney can excrete it.
the renal clearance of a drug can be calculated:
Cldrug =
UV = Urinary conc. UVol = ml/min
P
Plasma conc
GFR is 125 ml/min
• if the Cldrug is 125ml/min, it is filtered only
• if the Cldrug is <125ml/min, it is reabsorbed
• if the Cldrug is >125ml/min, it is secreted
* free drug only
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metabolism
• The purpose of drug metabolism is to render drugs
water soluble, so they can be excreted by the kidney
• The liver is the main organ of metabolism
• 2 types:
¶ phase 1: oxidation, reduction, hydrolysis
¶ phase 2: conjugation (glucuronide, sulphate)
oxidation via the cytochrome P450 system is important
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metabolism -2
reduced CYP450 picks up O2 and attaches it to the drug
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metabolism -3
• CYP3A lots of inhibitors and inducers
• CYP2D6 genetic variants (codeine)- 10% of caucasians
(Chinese produce less morphine from codeine and are also less
sensitive to morphine)
• CYP2C9 genetic variants (warfarin – 10-20% caucasians have a
variant isoform – can’t inactivate warfarin efficiently – more sensitive)
many drugs use more than one CYP; saturable pathways
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summary
• pharmacokinetics describes how the body handles
drugs
• drugs get into and out of the body
• to move from one compartment to another, the drug
must be lipid soluble which means non-ionized
• the kidney excretes water soluble drugs
• the liver metabolizes lipid soluble drugs
• CYP family is important
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