P2: Journey of a drug: the pharmacokinetic phase Flashcards
What happens in phase I metabolism?
Converts the parent drug to more polar metabolite by introducing or unmasking a functional group (OH, NH2, SH).
Usually loss of pharmacological activity.
Prepares drug for phase II.
Sometimes may be equally or more active than parent (prodrug).
What catalyses oxidation in phase I?
Cytochrome P450.
Uses molecular oxygen. - inserts 1 oxygen into substrate/drug. 2nd oxygen reduced to water.
Cyt p450 receives e- from NADPH.
What is CYP?
Heme containing enzyme.
Membrane bound protein/monooxygenase in smooth ER.
Must be associated in a complex w/ P450 reductase.
Important for steroidogenesis
How does electron flow to CYP?
NADPH –> FAD –> FMN –> CYP
(1st 3 happen in P450 reductase)
What is in the active site of CYP?
Mainly hydrophobic residues.
Haem/heme moiety anchored through cys sidechain
What is the main function of the CYP catalytic cycle?
Insert oxygen into a stable, hydrophobic compound.
What are the 5 steps in CYP450 catalytic cycle?
1) substrate binding
2) Oxygen binding
3) Oxygen scission
4) insertion of O into substrate.
5) release of product
What happens in the substrate binding?
A. the ferric CYP450 binds reversibly w/ substrate.
B. The ferric-substrate complex undergoes 1-e- reduction to give ferrous state.
What occurs in oxygen binding?
C. Reduced ferrous complex binds dioxygen as its 6th ligand.
What happens in oxygen scission?
D. 2nd e- is acquired from reductase generating a full negative charge on oxygen.
E. The resulting anion adds 2 protons and loses water, generating the Fe(IV) species or for simplicity Fe(V).
What happens in insertion of oxygen into the substrate?
G/F. Highly reactive Fe(IV)-porphyrin complex species abstracts a hydrogen atom from the substrate to give the carbon radical R attached to the Fe(IV)-OH species.
What can alkanes undergo?
Hydroxylation or dehydrogenation
What can generate epoxides?
Alkenes
How are epoxides made?
New bond forms between part of C from alkene (removes =).
Reduces the iron from Fe 4+ =O.
Free radical on other C.
Iron reduced again.
One e- from Fe-O goes to Fe.
One e- combines w/ radical on the carbon to form a second bond on oxygen.
Epoxide is formed.
Why are epoxides bad?
Toxic
Very reactive w/ DNA and proteins.
Carcinogenic
