ADMET: Metabolism: Metabolism-based DDIs

Objective

What are the 2 major types of potential CYP450-based interactions?

- Inhibition of (and substrate competition for) CYP450

- Induction of CYP450

Objective

What 2 things can inhibit CYP450?

- Azoles

- Grapefruit juice

Objective

Examples of azole antifungals that inhibit and compete for CYP3A4

-itraconazole

- ketoconazole

- other imidazole- and triazole-containing drugs (metronidazole and cimetidine)

What is the MOA of azole antifungals?

inhibition of a fungal P450 enzyme

Azole antifungals also display some inhibition and are substrates of....

human CYP3A4

What 3A4-metabolized drugs can azole-containing drugs decrease the metabolism of? (5)

- antiarrhythmics (quinidine)

- antiepileptics (cabamazepine, phenytoin)

- benzodiazepines (alprazolam, diazepam)

- cyclosporine

- warfarin

Some compounds in grapefruit juice _______________ and _____________ for CYP3A4

inhibit and compete

What are agents of concern when taking grapefruit juice (6)

- antiarrhythmics (quinidine)

- antiepileptics (cabamazepine, phenytoin)

- benzodiazepines (alprazolam, diazepam)

- cyclosporine

- warfarin

as well as lipid-lowering statins (atorvastatin)

Objective

What are 3 things that cause CYP450 induction? (induce CYP450)

- Barbiturates

- Rifamycins

- St. John's Wort

Objective

Barbituric acid examples that are known inducers of CYP3A4 (2)

- phenobarbital

- butabarbital

Barbituric acids can ______________ the rate of metabolism of drugs that are ___________________

- increase
- CYP3A4 substrates

Barbituric acids can increase the rate of metabolism of drugs that are CYP3A4 substrates, including: (4)

- Beta-blockers (atenolol, proranolol)

- Oral contraceptives (estrogen-progestin combinations)

- Quinidine

- Warfarin

Objective

Rifamycins that are known inducers of the 3A4P450 isoform (3)

- rifampin

- rifabutin

- rifapentine

rifampin has the most issues here

Rifamycins can increase the rate of metabolism of drugs that are CYP3A4 substrates, including: (4)

•Beta-blockers (atenolol, propranolol)

•Oral contraceptives (estrogen-progestin combinations)

•Quinidine

•Warfarin

St John's Wort has compounds that are...

potent CYP3A4 inducers

Objective

In case of DDI's due to CYP inhibition, what are potential dosage adjustments?

CYP inhibitors decrease rate of metabolism

- lead to increased level of drug in blood

- higher concentration remains in system

- lowering dose of medication so it is not as potent and concentration does not build up

Objective

In case of DDI's due to CYP induction, what are potential dosage adjustments?

increases rate of metabolism

- rapidly metabolizes medications

- reduces their effectiveness and results in therapeutic failure

- increasing dose of medication for more of an effect