415 pht 6

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‫المحاضره السادسه‬
Hepatic clearance and elimination
Drug biotransformation reactions:
- Metabolism is the major mechanism for elimination of drugs from
body.
 Some drugs are eliminated unchanged entirely by kidneys (few
drugs).
 Biotransformation provides a mechanism for:
1. Riding the body of undesirable foreign compounds and
drugs.
2. It also provides a means of producing active and toxic
compounding.
 The administered drug sometimes is an inactive prodrug
by active metabolism converts to pharmacologically active.
 Often both drug and its metabolites are active.
 The most common routs of drug metabolism are:
Oxidation, reduction, hydrolysis and conjugation.
 Frequently, a drug undergoes metabolism by several competing
pathways.
 Example of biotransformation reactions and pharmacologic
activity of metabolites.
1. Active drug to inactive metabolite.
 Amphetamine deamination phenyl acetone.
 Phenobarbital hydroxylation hydroxyPhenobarbital.
2. Active drug to active metabolite.
 Codeine demethylation morphine
 Procainamide acetylation N-acetylProcainamide
 Phenylbutazone hydroxylation oxyphenbutazone
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3- Inactive drug
to
active metabolite:
Hydrolysis
Hetacillin
ampicillin
azo reduction
Sulfasalazine
sulfapyridine
4- Active drug to reactive intermediate:
Aromatic hydroxylation
Acetaminophen
reactive metabolite
* Rate constant of elimination:
- The rate constant of elimination (k) is the sum of the first order rate
constant for metabolism (km) and the first order rate constant for
excretion (ke)
K=ke+km
The percentage of total drug metabolized:
% of drug metabolized = (km/k) x100
The rate constant of metabolism (km), non renal drug elimination is
difficult to measure directly and is found by:
Km= k – ke
Percent of drug metabolized:
 For most drugs the fraction of a given metabolites is constant.
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 EX: consider a drug with two major metabolites (A, B) and also
eliminated by renal excretion.
 Assume that 100 µg of the drug was given to a patient and the
drug is completely absorbed (f = 1)
 The complete urine collection was done and the quantities are
shown As:
Km A
Drug (100 µg)
Km B
Ke
Metabolite A (10µg)
Metabolite B (20µg)
Unchanged drug in urine (70µg)
 From a clinical viewpoint, the percentage of drug excretion and
metabolism constitute useful information.
 If the renal excretion pathway because impaired as in the case of
kidney disorder, then the drug will be eliminated primarily by
hepatic metabolism.
 The reverse is true if liver function decline.
 In the above example , t ½ of drug = 2 hrs and k = 0.347 hrˉ¹
 To determine the renal excretion rate constant , the following
relationship is used :
Ke / K = Du /total dose absorbed = Du / FD
Where:
D u = total amount of unchanged drug recovered in urine
K e = 0.347 x 70 / 100 =0.243 hrˉ¹
% of drug excretion = ke / k x 100 = 0,243 x 100 = 70%
Alternatively, since 70 (micro gram) of unchanged drug recovered and of
the total dose of 100 micro grams
% of drug excretion = (70/100) x 100= 70%
% of drug metabolism = 100 -70 = 30%
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* In this example, if the renal excretion becomes totally impaired, t1/2
can be determined:
K – km = ke
But ke = zero
So, k = km
K = km = 0.104 hr-1
t1/2=0.693/0.104 = 6-7 hr
Liver function test:
- Bromsulphthalein (BSP) is used for determination of secretory function
of liver.
- Pathologist data could be either due to damage of liver paranchymal
cell or caused by icteus.
- 5 mg / kg BSP is administered I.V. after 3 minutes and after 45 minutes
blood sample are taken and BSP is determined in serum.
BSP retention = (extinction of 45 minutes sample / extinction of 3
minutes sample) x 100
No liver damage: up to 5% BSP retention
Mild liver damage: 5% - 25% BSP retention
Sever liver damage 25% - 75% BSP retention
First-pass effects:
 Drugs which are highly metabolized by liver or by intestinal
mucosal cells demonstrate poor systemic availability when are
given orally.
 This rapid metabolism of an orally drug administered prior to
reaching general circulation
first pass effects or presystemic
circulation.
 This first-pass effects may be suspected when there is a lack of
parent or intact drug in the systemic circulation after oral
administration.
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 In this case, AUC for a drug given orally is less than that for the
same drug is given I.V.
 Examination of absolute bioavailability (F) May reveal evidence of
drug being removed by liver due to first pass effect.
F: is less than 1 if the drug undergoes first-pass effect.
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