415 pht 6

‫المحاضره السادسه‬
Hepatic clearance and elimination
Drug biotransformation reactions:
- Metabolism is the major mechanism for elimination of drugs from
 Some drugs are eliminated unchanged entirely by kidneys (few
 Biotransformation provides a mechanism for:
1. Riding the body of undesirable foreign compounds and
2. It also provides a means of producing active and toxic
 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
 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
3- Inactive drug
active metabolite:
azo reduction
4- Active drug to reactive intermediate:
Aromatic hydroxylation
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)
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.
 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
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
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%
* 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
 This first-pass effects may be suspected when there is a lack of
parent or intact drug in the systemic circulation after oral
 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.