Medical Pharmacology – Chapter 6 – Elimination of drugs:
biotransformation and excretion
Elimination; determine the length of time that a drug remains in the body and which
concentrations can be reached in tissues.
Biotransformation (anywhere in the body, mostly in the liver);
Chemical reactions that occur in the body whereby the structure of foreign
substances produced is changed. Products that develop are called metabolites.
Enzyme occurring in organelles/sites of the enzyme reticulum (microsomes)
Biotransformation divided into 2;
Non-synthetic biotransformation reactions; phase I reactions. They catalyse
mostly oxidation, reduction or hydrolytic reactions
o Microsomal non-synthetic reactions; mostly occur in liver cells by
microsomal enzymes, which are associated with smooth endoplasmic
reticulum.
Less substrate specificity
Convert only endogenous substances
Not strictly lipophilicity
Most common reactions are microsomal oxidation reaction performed
by mixed function oxidase (MFO), in which cytochrome P-450 is the
final oxidase.
o Non-microsomal reactions; mostly occur in liver but also other tissues
and plasma.
More substrate specificity
Convert both foreign as well as endogenous substances
Sufficient lipophilicity
Examples:
Alcohol-dehydrogenase, that oxidises alcohols and aldehydes
Monoamine-oxidase (MAO) and other enzymes, that oxidatively
deaminate only primary amines, whereby aldehydes or carbon
acids are produced
Esterases, split ester bonds by hydrolysis. Aspirin has ester
bond.
Synthetic biotransformation reactions; phase II reactions. Drugs result from
non-synthetic reaction can bound another molecule (conjugating agent) via
conjugation reaction.
The conjugated agent is produced by the body itself. To conjugate, the
substrate needs to possess a conjugation site (-OH, -NH2, -SH, -COOH).
o Microsomal conjugation reactions; mostly occur in liver, but also in
other tissues
Important reactions:
Glucuronide synthesis
Glycine synthesis
, o Non-microsomal conjugation reactions; occur in various tissues.
Imporant reactions:
Acetylation
sulfate conjugation
Methylation
Purpose is to make the drug more hydrophilic so excreted via the kidney
Biotransformation will lead to biologically inactive products but not always.
There will be products that still have the same activity or that are more or less toxic.
Drug can be subjected to different biotransformation reactions (both synthetic and
non-synthetic) creating different metabolites
Metabolites fromed by non-synthetic reactions can undero conjugation reactions
next. Biotransformation may also be used to convert inactive compounds (pro-drug)
in an active substance.
Biotransformation involve enzyme reactions. Rate of enzyme reaction:
V = Vmax * S /Km + S
--> lover Km is greater affinity
Biotransformation follow first-order reaction process (for most drugs)
Speed is directly proportional to the drug concentration at that time
V = Vmax*S/ Km = K*S
Biotransformation follow zero-order reaction process
Speeds is maximal and thus independent to the substrate concentration
When substrate concentration has dropped sufficiently zero-order process
turns into first order process
V=Vmax
Factors that affect biotransformation of drugs
Enzyme inhibition; process in which activity of the microsomal
biotransformation enzymes can be decreased.
o Competitive: The inhibitor bind to active site of the enzyme and
competes with the substrate. Increasing the substrate concentration will
remove the inhibitor from the enzyme.
The Vmax of the enzyme does not change, but will only be reached in
the presence of a competitive inhibitor at a higher substrate
concentration
Include monoamine oxidase inhibitors (MAO)
o Non-competitive the inhibitor bind to nonactive site of the enzyme
The Vmax of the enzyme decreases, which reduces the rate at which
the substrate is converted. An increase in substrate concentration has
no effect on the inhibition.
Include toxic substances
biotransformation and excretion
Elimination; determine the length of time that a drug remains in the body and which
concentrations can be reached in tissues.
Biotransformation (anywhere in the body, mostly in the liver);
Chemical reactions that occur in the body whereby the structure of foreign
substances produced is changed. Products that develop are called metabolites.
Enzyme occurring in organelles/sites of the enzyme reticulum (microsomes)
Biotransformation divided into 2;
Non-synthetic biotransformation reactions; phase I reactions. They catalyse
mostly oxidation, reduction or hydrolytic reactions
o Microsomal non-synthetic reactions; mostly occur in liver cells by
microsomal enzymes, which are associated with smooth endoplasmic
reticulum.
Less substrate specificity
Convert only endogenous substances
Not strictly lipophilicity
Most common reactions are microsomal oxidation reaction performed
by mixed function oxidase (MFO), in which cytochrome P-450 is the
final oxidase.
o Non-microsomal reactions; mostly occur in liver but also other tissues
and plasma.
More substrate specificity
Convert both foreign as well as endogenous substances
Sufficient lipophilicity
Examples:
Alcohol-dehydrogenase, that oxidises alcohols and aldehydes
Monoamine-oxidase (MAO) and other enzymes, that oxidatively
deaminate only primary amines, whereby aldehydes or carbon
acids are produced
Esterases, split ester bonds by hydrolysis. Aspirin has ester
bond.
Synthetic biotransformation reactions; phase II reactions. Drugs result from
non-synthetic reaction can bound another molecule (conjugating agent) via
conjugation reaction.
The conjugated agent is produced by the body itself. To conjugate, the
substrate needs to possess a conjugation site (-OH, -NH2, -SH, -COOH).
o Microsomal conjugation reactions; mostly occur in liver, but also in
other tissues
Important reactions:
Glucuronide synthesis
Glycine synthesis
, o Non-microsomal conjugation reactions; occur in various tissues.
Imporant reactions:
Acetylation
sulfate conjugation
Methylation
Purpose is to make the drug more hydrophilic so excreted via the kidney
Biotransformation will lead to biologically inactive products but not always.
There will be products that still have the same activity or that are more or less toxic.
Drug can be subjected to different biotransformation reactions (both synthetic and
non-synthetic) creating different metabolites
Metabolites fromed by non-synthetic reactions can undero conjugation reactions
next. Biotransformation may also be used to convert inactive compounds (pro-drug)
in an active substance.
Biotransformation involve enzyme reactions. Rate of enzyme reaction:
V = Vmax * S /Km + S
--> lover Km is greater affinity
Biotransformation follow first-order reaction process (for most drugs)
Speed is directly proportional to the drug concentration at that time
V = Vmax*S/ Km = K*S
Biotransformation follow zero-order reaction process
Speeds is maximal and thus independent to the substrate concentration
When substrate concentration has dropped sufficiently zero-order process
turns into first order process
V=Vmax
Factors that affect biotransformation of drugs
Enzyme inhibition; process in which activity of the microsomal
biotransformation enzymes can be decreased.
o Competitive: The inhibitor bind to active site of the enzyme and
competes with the substrate. Increasing the substrate concentration will
remove the inhibitor from the enzyme.
The Vmax of the enzyme does not change, but will only be reached in
the presence of a competitive inhibitor at a higher substrate
concentration
Include monoamine oxidase inhibitors (MAO)
o Non-competitive the inhibitor bind to nonactive site of the enzyme
The Vmax of the enzyme decreases, which reduces the rate at which
the substrate is converted. An increase in substrate concentration has
no effect on the inhibition.
Include toxic substances
