Midterm 1: P450 Drug Metabolism DDIs: Induction

Question 1

drug-drug interaction (DDI) definition

Answer 1

• two drugs, each of which is safe and efficacious alone at their respective doses, produce either a toxic or sub-therapeutic effect when given in combination.

Question 2

Metabolism-based DDIs:

Answer 2

• occur as the result of drug induced changes in drug metabolizing capacity (metabolic clearance).
• Metabolic drug-drug interactions, when anticipated, can often be managed or avoided by:
  • 1. Selecting a different non-interacting pair
  • 2. Dose changes of the object drug adjustments at the initiation and termination of polytherapy.

Question 3

Object Drug:

Answer 3

The drug whose metabolism has been altered by the Interactant Drug.

Question 4

Interactant Drug:

Answer 4

The drug that is causing a change in the activity or amount of the enzymes that control the metabolic clearance of the object drug.

Question 5

Table: Metabolism DDI

• Effect of an Interactant Drug on Active P450 Levels
• Condition
• Effect of Interactant Drug on Object Drug Clearance (Cl)
• Effect of Interactant Drug on Object Drug Half-life (t1/2)

Answer 5

Question 6

Graph: Metabolism based DDI

Answer 6

• More worried by inhibitory effects than inductive effects because much less likely to increase amount of enzyme by 100%
• Increase clearance by increasing the amount of enzyme.
• Double the Clearance (100% change, drug concentration lowered by factor of 2)
• C=D/(CL*t)

Question 7

Alfentanil, Rifampicin, and Troleandomycin

Answer 7

• Alfentanil (synthetic opiod for parenteral use) metabolic clearance via N-dealkylation to nor- alfentanil by CYP3A4 (90%). Other drugs in the class are fentanyl and remifentanil (also CYP3A substrates).
• Rifampicin is an antibacterial used in the treatment of tuberculosis. It is a general and potent inducer of P450 enzymes including CYP3A4, CYP2C9 and CYP2C19.
• Troleandomycin (TAO) is an erythromycin analog and a potent selective inhibitor of CYP3A4 in vivo. Erythromycin and clarithromycin (another erythromycin analog( are also a selective inhibitors of CYP3A4 and produce significant interactions but are not as potent as TAO at normal doses.

Question 8

Let’s look at another example using a different object drug midazolam i.v. and the same two interactant drugs.

Answer 8

• So we see exactly the same pattern of effect on half-life and clearance.
• CYP3A4 controls about 90% of midazolam clearance.
• magnitude of the effect of induction is less than the magnitude of effect for Troleandomycin. Erythromycin is also a clinically significant inhibitor of CYP3A4.
• Corollary: If a group of object drugs are metabolized significantly by a given enzyme then the effect of a given interactant drug on clearance should be seen for all of those object drugs.

Question 9

Induction of P450 Enzymes

Answer 9

• Induction of P450 enzyme levels normally takes days to reach full effect.
• Similarly de- induction due to removal of an inducing agent also takes days to reach completion.
  
  • If the levels of the P450 enzyme(s) that are responsible for metabolizing an object drug are induced by administration of an interactant drug, then the dose of the object drug may need to be altered in order to achieve safe therapeutic concentrations.

Question 10

Induction of P450 Enzymes: 2 scenarios

Answer 10

• Inducer drug makes object drug cleared faster and makes subtherapeutic concentrations
  
  • If the increase in metabolic capacity is not recognized when an interactant drug is added to a therapeutic regimen of the object drug and appropriate steps taken, the levels of the object drug may fall to subtherapeutic levels as enzyme levels and metabolic capacity increase.
• Removing an interacting inducer from a therapeutic regimen
  
  • ​Conversely when an individual is stabilized on a multi drug regimen and the interactant inducing drug is removed, the levels of the object drug may increase to toxic levels as enzyme levels and metabolic capacity falls.

Question 11

Mechanisms of Induction using CYP1A2 as an example

Answer 11

• inducing agent binds to a soluble receptor in the cell cytosol or nucleus.
• receptor-drug complex binds to upstream regions of the gene that codes for a P450 enzymes known as XRE’s (xenobiotic response elements) and turns on transcription.
• The AHR receptor can increase the transcription of many genes.
• Note that this leads to increases in protein synthesis and exerts control on multiple processes.
• Binding of inducing agents (TCDD, omeprazole, polycyclic aromatic hydrocarbons) to the AhR receptor leads to increased transcription of the DNA coding for CYP1A2.

Question 12

Induction of the CYP1A2 enzymes by PAH’s in cigarette smoke

Answer 12

• two-fold induction of CYP1A2 levels and a maximum increase in metabolic clearance of 2 fold.
• Theophylline (asthma) cleared by CYP1A2 dependent metabolism. Dose 60% higher in smokers than in the normal population due to induction of CYP1A2. About 60% of the clearance of theophylline is due to CYP1A2.
• Clozapine (antipsychotic) after initiation of clozapine therapy institutionalized patients often quit smoking. In this case the dose of clozapine must be decreased 2-3 fold which means that most of the metabolism of clozapine is via CYP1A2.
• 90% of caffeine clearance is due to CYP1A2. “Why can’t I sleep?” Answer is cut down on the coffee.

Question 13

ther receptors can be activated by inducers to turn on expression of other P450 enzymes. (Table)

Answer 13

Question 14

CYP3A4 Induction

Answer 14

• Major inducing drugs and herbals are Carbamazepine, Phenytoin, Barbituates, St John’s Wort, Dexamethasone, Rifampin
• Many, many object drugs including the statins (simvistatin), oral contraceptive, estrogens (ethinyl estradiol), the HIV protease inhibitors (saquinavir).
• Example: Effect of the object interactant drug phenytoin (an anticonvulsant) on the pharmacokinetics of the object drug cyclosporin (an important immunosuppressant) metabolized by CYP3A4.

Question 15

effect of rifampin on bioavailablity of an oral dose of midazolam

Answer 15

• really large
• Notice the dramatic fall in MDZ AUC. MDZ has a big first pass effect (30% of drug reaches systemic circulation).
• CYP3A in the enterocytes and the liver each contribute to the first pass effect roughly equally.
• Since these tissues are arranged in series to oral drug getting to the systemic circulation, a two fold induction of CYP3A4 in each tissue would result in a 4 fold drop in bioavailability.
• Thus the magnitude of the effects of induction on active enzyme levels in each of the liver and enterocyte is magnified with respect to systemic bioavailability for orally administered drugs.
• Theoretically, a two fold increase in enzyme levels in each location (would result in a doubling in clearance by each site) would reduce bioavailability by around four fold. Naturally the real world is much more complicated than that but the general concept is valid.

Question 16

CYP3A4 Induction by carbamazepine (epilepsy) and oral contraceptives.

Answer 16

• “Our findings confirm a long-standing clinical suspicion; a low-dose OC performs poorly, in terms of ovulation suppression and cycle control, during coadministration of a common dose of CBZ. Some clinicians recommend extended cycle regimens with OCs containing 50 lg of EE and a shortened pill-free interval.”
• Gail Anderson insists that epileptics should not rely on O.C. for birth control. She is very skeptical of simply increasing the dose to match the metabolism due to other effects of the o.c.’s like clotting disorders.

Question 17

CYP2C9 Induction:

Answer 17

• Inducers: rifampacin, phenytoin, barbituates
• Object drug:warfarin
• Effect of rifampinon warfarin levels and pharmacological effect.
  
  • A drop from 100% activity (10-11 second clotting time) to the desired effect (16 to 20 second clotting time) is achieved by a chronic mean daily warfarin dose of 10 mg.
  • Note that warfarin levels (controlled by CYP2C9) plummet when rifampin is added to therapy and the prothrombin activity returns to normal (10 second clotting time). Now the patient will receive no benefit from warfarin unless the dose is adjusted upwards or rifampin is removed.
• Induction of CYP2C9 enzymes is via binding to the CAR receptor.