Pharmacokinetics
Chapter 1 and 2
Pharmacology: studies how a drug affects a biological system and how the body responds to the
drug.
Consist of:
Pharmacodynamics → drug response
“What is the drug doing to the body?”
Pharmacokinetics → study of the fate of a drug in the body in time
“What is the body doing to the drug?”
→ ADME
• Absorption → how will it get in?
• Distribution → where will it go to?
• Elimination → how does it leave the body?
• Excretion & metabolism
Absorption: Administration routes (terminology)
Intravascular → directly into blood
• Intravenous injection/infusion
• Intra-arterially
Extravascular → need absorption
Parenteral → does not pass gastrointestinal tract
• Intravenous/intra-arterial
• Intramuscular
• Sub-/intracutaneous
• Pulmonary
• Intranasal
• Intra-/transdermal
• Inhalation
Enteral → via gastrointestinal tract
• Oral
• Rectal
• Sublingual
• Buccal
Local/regional → directly onto skin, mucosa, cerebrospinal fluid, pleural or peritoneal cavity
• Cutaneous/nasal/vaginal/ocular
Systemic → directly into system
Distribution
• Effects
• Adverse effects
• Toxic effects (toxicokinetics)
• Accumulation
,Enterohepatic cycle: a cycling of drugs between your enterocytes
(in the gut and the intestine) and the hepatic (within the liver).
• Drug is not excreted!!! → can be taken up again by the cycle
• Recirculated
Drug is transported back via the intestine → the portal vein →
liver → blood stream
• Typically belongs to distribution!!!
First pass effect
• Typically belongs to absorption
• Has to do with the bioavailability
• Passes only 1 time
Elimination
Metabolism → primary occurring in the liver
Excretion → most of the drugs are being excreted via the kidneys
• Feces/skin/lungs
Metabolites: compounds formed from the drug usually by enzymatic reactions (cytochroom P450
enzymes)
• Inactive and active (activity on their own
Plasma concentration-time curve
Often used in pharmacokinetics
• Samples from body
→ blood samples from veins, feces, samples of urine
Curve depends on administration route
1) If there is absorption
• First increase in concentration till a certain time → then decay
3) When the drug is injected to the blood stream immediately
• High concentration on t = 0 → then decay
5) Infusion or with devices that have slow release
• Concentration t = 0 is zero → then an increase in concentration till it is even
Therapeutic window: concentration that fall between the minimal and maximal concentration of a
drug to obtain a certain effect (mostly with plasma drug concentration).
,Therapeutic drug monitoring
Measure plasma concentration → for drugs with a narrow therapeutic window
Blood: plasma (including plasma proteins) + cells (RBC, WBC, platelets); with clotting factors
• ±5-6L
Plasma: water (90%) + ions + lipids + plasma proteins; no cells
• 55%bloedvolume=±3L
Serum: plasma (including plasma proteins) but without clotting factors (fibrinogen/fibrin)
• Centrifuge blood; no clotting factors
Models used in pharmacokinetics
1. Equations
2. Physiologic models
3. Compartmental models → together with equations
Correlate plasma concentration with effect → correlate
pharmacokinetics and pharmacodynamics
• Pharmacokinetics → concentration vs time
• Pharmacodynamics → concentration vs effect
• PK/PD → effect vs time
Direct effect or no direct response.
PK/PD response is different for every patient
Related to PK:
• Gender, race, body size
• Renal/hepatic function
• Gastric pH
• Drug-drug interactions
• Environmental factors
• Type/degree/concomitant diseases
• Drug metabolism polymorphisms
• Medication compliance
Related to PD:
• Gender, race
• Drug-drug interactions
• Environmental factors
• Type/degree/concomitant diseases
• Placebo effect
• Drug receptor or enzyme polymorphisms
• Tolerance, tachyphylaxis
Medical compliance / adherence
Non-adherence to prescribed medication is a major source of
variability in drug therapy.
e.g. when a patient does not take a drug properly.
• Digital medicine system
, Digoxin case
Woman (55 y, 70 kg)
Medication used for several years:
1 dd 0.375 mg digoxin (atrial fibrillation)
Lately patient has complains about constant feeling of nausea and diarrhea
-> GP consult -> GP: After exclusion of other diseases, suspects problems with
the digoxin administration
Q: Why and what should be done?
In hospital pharmacy:
1. Assess plasma concentration of digoxin
→ Blood sample 3 hours after the last tablet; blood concentration: 3.8μg.l-1 → too high
drug concentration
2. Recalculate kinetics in this patient
V1 and V2 → parameters for distribution
CLm and CL12 → parameters for elimination (lower elimination → higher concentration of
drug inside the body)
Ka_po and F_po → parameter for absorption (higher absorption → higher bioavailability)
→ from 0.375mg to 0.19mg
Q: What can be the reason of the increased digoxin concentrations?
Higher absorption → more drug is going in
• Change in transporters → e.g. other compound that interferes with transporters
Lower excretion → when process is inhibited
Chapter 3
Therapeutic effect depends on drug concentration
→ you want to keep the dose as low as possible and still obtain a good effect
Intravenous bolus dose
→ means that you give an injection quickly (enters systemic circulation immediately)
• All the blood is going to the bloodstream
→ no absorption phase (_DME)
• Easier to analyze
Plasma drug concentration time-profile
Plasma normal human being → around 4 liters
Note order of magnitude of concentration (start concentration).
Assumed situation → only in the bloodstream
Actual situation → sometimes drugs distribute to other tissue of the body
Chapter 1 and 2
Pharmacology: studies how a drug affects a biological system and how the body responds to the
drug.
Consist of:
Pharmacodynamics → drug response
“What is the drug doing to the body?”
Pharmacokinetics → study of the fate of a drug in the body in time
“What is the body doing to the drug?”
→ ADME
• Absorption → how will it get in?
• Distribution → where will it go to?
• Elimination → how does it leave the body?
• Excretion & metabolism
Absorption: Administration routes (terminology)
Intravascular → directly into blood
• Intravenous injection/infusion
• Intra-arterially
Extravascular → need absorption
Parenteral → does not pass gastrointestinal tract
• Intravenous/intra-arterial
• Intramuscular
• Sub-/intracutaneous
• Pulmonary
• Intranasal
• Intra-/transdermal
• Inhalation
Enteral → via gastrointestinal tract
• Oral
• Rectal
• Sublingual
• Buccal
Local/regional → directly onto skin, mucosa, cerebrospinal fluid, pleural or peritoneal cavity
• Cutaneous/nasal/vaginal/ocular
Systemic → directly into system
Distribution
• Effects
• Adverse effects
• Toxic effects (toxicokinetics)
• Accumulation
,Enterohepatic cycle: a cycling of drugs between your enterocytes
(in the gut and the intestine) and the hepatic (within the liver).
• Drug is not excreted!!! → can be taken up again by the cycle
• Recirculated
Drug is transported back via the intestine → the portal vein →
liver → blood stream
• Typically belongs to distribution!!!
First pass effect
• Typically belongs to absorption
• Has to do with the bioavailability
• Passes only 1 time
Elimination
Metabolism → primary occurring in the liver
Excretion → most of the drugs are being excreted via the kidneys
• Feces/skin/lungs
Metabolites: compounds formed from the drug usually by enzymatic reactions (cytochroom P450
enzymes)
• Inactive and active (activity on their own
Plasma concentration-time curve
Often used in pharmacokinetics
• Samples from body
→ blood samples from veins, feces, samples of urine
Curve depends on administration route
1) If there is absorption
• First increase in concentration till a certain time → then decay
3) When the drug is injected to the blood stream immediately
• High concentration on t = 0 → then decay
5) Infusion or with devices that have slow release
• Concentration t = 0 is zero → then an increase in concentration till it is even
Therapeutic window: concentration that fall between the minimal and maximal concentration of a
drug to obtain a certain effect (mostly with plasma drug concentration).
,Therapeutic drug monitoring
Measure plasma concentration → for drugs with a narrow therapeutic window
Blood: plasma (including plasma proteins) + cells (RBC, WBC, platelets); with clotting factors
• ±5-6L
Plasma: water (90%) + ions + lipids + plasma proteins; no cells
• 55%bloedvolume=±3L
Serum: plasma (including plasma proteins) but without clotting factors (fibrinogen/fibrin)
• Centrifuge blood; no clotting factors
Models used in pharmacokinetics
1. Equations
2. Physiologic models
3. Compartmental models → together with equations
Correlate plasma concentration with effect → correlate
pharmacokinetics and pharmacodynamics
• Pharmacokinetics → concentration vs time
• Pharmacodynamics → concentration vs effect
• PK/PD → effect vs time
Direct effect or no direct response.
PK/PD response is different for every patient
Related to PK:
• Gender, race, body size
• Renal/hepatic function
• Gastric pH
• Drug-drug interactions
• Environmental factors
• Type/degree/concomitant diseases
• Drug metabolism polymorphisms
• Medication compliance
Related to PD:
• Gender, race
• Drug-drug interactions
• Environmental factors
• Type/degree/concomitant diseases
• Placebo effect
• Drug receptor or enzyme polymorphisms
• Tolerance, tachyphylaxis
Medical compliance / adherence
Non-adherence to prescribed medication is a major source of
variability in drug therapy.
e.g. when a patient does not take a drug properly.
• Digital medicine system
, Digoxin case
Woman (55 y, 70 kg)
Medication used for several years:
1 dd 0.375 mg digoxin (atrial fibrillation)
Lately patient has complains about constant feeling of nausea and diarrhea
-> GP consult -> GP: After exclusion of other diseases, suspects problems with
the digoxin administration
Q: Why and what should be done?
In hospital pharmacy:
1. Assess plasma concentration of digoxin
→ Blood sample 3 hours after the last tablet; blood concentration: 3.8μg.l-1 → too high
drug concentration
2. Recalculate kinetics in this patient
V1 and V2 → parameters for distribution
CLm and CL12 → parameters for elimination (lower elimination → higher concentration of
drug inside the body)
Ka_po and F_po → parameter for absorption (higher absorption → higher bioavailability)
→ from 0.375mg to 0.19mg
Q: What can be the reason of the increased digoxin concentrations?
Higher absorption → more drug is going in
• Change in transporters → e.g. other compound that interferes with transporters
Lower excretion → when process is inhibited
Chapter 3
Therapeutic effect depends on drug concentration
→ you want to keep the dose as low as possible and still obtain a good effect
Intravenous bolus dose
→ means that you give an injection quickly (enters systemic circulation immediately)
• All the blood is going to the bloodstream
→ no absorption phase (_DME)
• Easier to analyze
Plasma drug concentration time-profile
Plasma normal human being → around 4 liters
Note order of magnitude of concentration (start concentration).
Assumed situation → only in the bloodstream
Actual situation → sometimes drugs distribute to other tissue of the body
