OMEPRAZOLE
INTRODUCTION
= inhibits gastric acid secretion
MW = 345.42
- Soluble in ethanol and methanol
- Only slightly in water
- Acceptable stability
- rapidly degraded in acid media
- micro tablets
pharmacokinetics
- will only arise absorption when leaving stomach
- rapid absorption
- will occur 3,5h post admin
- Peak plasma concentration and AUC occurs with doses greater than 40 mg
- AUC beyond 40mg higher exposure than expected
o 30-40: low due to presystemic metabolism
- plasma half-life is 0.5 to 1 hour
- the total body clearance is 500-600 mL/min.
- Protein binding is approximately 95%.
- chronic hepatic disease,
o the bioavailability increased to approximately 100% compared to an I.V. dose,
reflecting decreased first-pass effect
o plasma half-life of the drug increased to nearly 3 hours compared to the half-life in
normals of 0.5-1 hour
o Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in
normal subjects.
Very similar compared to healthy individuals
- Differences in ages
o Decreased elimination in elderly
Bioavailability increased
o Paeds
Lower AUC <6 years compared to 6-16 years
Pharmacodynamics
- New class of compounds in that time
o Doesn’t exhibit the anticholinergic or histamine antagonistic
- one hour two hours
- 50% of inhibition lasts up to 72
- Compare kinetics to dynamics
, o Way longer than we expect
o Prolonged binding to the target!
Drug interactions
- May be prolonged in combi with other drugs
o In normal = no interaction
o If we look at the clinical interaction impact of the cyps
o Increase in omeprazole larger than expected from singular admin
o QT prolongation and torsades de pointes
Carci and reproductive
- 2 in rats
o Occurrence of carcinoid in male and female
o Normally not visible in control animals
o 2nd year = effect was decreased
o 3 year study found no effects
Pregnancy
- In tox studies 56x human dose
o Now = exposure no dose
o Early = dose comparison
o At about 56 times higher than human dose = no effect
o Dose related increase in rabbits = embryo lethality, fetal resorptions and pregnancy
BASED ON MW WHAT IS YOUR OPINION ON ORAL ABSORPTION?
- 345.42
o Lipinsky rule of 5 = 200-500 has a good oral absorption
Good Numbers
MW 200-500
Log P (lipofobicity) 1-5
H bond acceptors >10
H bond donors 5-10
Rotable bonds <7
Polar surface <100 Å
- Very slightly soluble in water = bad
o Need a bit of lipophilicity to pass the membrane but need some solubility to pass
enterocytes
- Dependent on pH
INTRODUCTION
= inhibits gastric acid secretion
MW = 345.42
- Soluble in ethanol and methanol
- Only slightly in water
- Acceptable stability
- rapidly degraded in acid media
- micro tablets
pharmacokinetics
- will only arise absorption when leaving stomach
- rapid absorption
- will occur 3,5h post admin
- Peak plasma concentration and AUC occurs with doses greater than 40 mg
- AUC beyond 40mg higher exposure than expected
o 30-40: low due to presystemic metabolism
- plasma half-life is 0.5 to 1 hour
- the total body clearance is 500-600 mL/min.
- Protein binding is approximately 95%.
- chronic hepatic disease,
o the bioavailability increased to approximately 100% compared to an I.V. dose,
reflecting decreased first-pass effect
o plasma half-life of the drug increased to nearly 3 hours compared to the half-life in
normals of 0.5-1 hour
o Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in
normal subjects.
Very similar compared to healthy individuals
- Differences in ages
o Decreased elimination in elderly
Bioavailability increased
o Paeds
Lower AUC <6 years compared to 6-16 years
Pharmacodynamics
- New class of compounds in that time
o Doesn’t exhibit the anticholinergic or histamine antagonistic
- one hour two hours
- 50% of inhibition lasts up to 72
- Compare kinetics to dynamics
, o Way longer than we expect
o Prolonged binding to the target!
Drug interactions
- May be prolonged in combi with other drugs
o In normal = no interaction
o If we look at the clinical interaction impact of the cyps
o Increase in omeprazole larger than expected from singular admin
o QT prolongation and torsades de pointes
Carci and reproductive
- 2 in rats
o Occurrence of carcinoid in male and female
o Normally not visible in control animals
o 2nd year = effect was decreased
o 3 year study found no effects
Pregnancy
- In tox studies 56x human dose
o Now = exposure no dose
o Early = dose comparison
o At about 56 times higher than human dose = no effect
o Dose related increase in rabbits = embryo lethality, fetal resorptions and pregnancy
BASED ON MW WHAT IS YOUR OPINION ON ORAL ABSORPTION?
- 345.42
o Lipinsky rule of 5 = 200-500 has a good oral absorption
Good Numbers
MW 200-500
Log P (lipofobicity) 1-5
H bond acceptors >10
H bond donors 5-10
Rotable bonds <7
Polar surface <100 Å
- Very slightly soluble in water = bad
o Need a bit of lipophilicity to pass the membrane but need some solubility to pass
enterocytes
- Dependent on pH
