Clarifications of Lecture #36- Drug Interactions I

Mutual Effects

Mutual Effects * Drug Displaced Unbound Bound 100% Drug * 0% C D C D C Low Extraction Ratio IV or Oral High Extraction Ratio IV High Extraction Ratio Oral 100% Drug * 0% C D C D C D Clearance [Drug]plasma

Mutual Effects * Drug Displaced Unbound Bound [Drug] * C D C D C D Low Extraction Ratio IV or Oral High Extraction Ratio IV High Extraction Ratio Oral [Drug] * C D C D C D * Unbound [Drug] the same for Low Extraction Ratio and High Extraction Ratio Oral.

Mutual Effects D = Displaced C = Control Total Unbound

Mutual Effects anti-seizure anti-seizure Extraction Ratio? https://en.wikipedia.org/wiki/Phenytoin https://en.wikipedia.org/wiki/Valproate http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884335/ * This is consistent with increased clearance following displacement from the plasma protein binding site of a highly bound drug with a low hepatic extraction ratio [34]. anti-seizure Extraction Ratio?

Aside: Question of Effect of Ethanol and Benzodiazepines on an Action Potential

Action Potential

Action Potential Depolarization Repolarization

Channel Types Chloride Channels Potassium Channels Sodium Channels Voltage-gated Resting Potential (-70 mV) Ligand-gated Chloride Channels GABAA Receptor Potassium Channels Sodium Channels Voltage-gated/Ligand-gated

Effect of Ethanol or Benzodiazepines Threshold Hyperpolarization Hyperpolarization effect of ethanol/benzodiazepines More difficult to initiate action potentials. 15 mV difference  45 mM difference.

Lecture #37 Drug Interactions II

Interaction Types Mutual Effects Bidirectional Effects Competing for the same target Bidirectional Effects Unidirectional Effects AB Beneficial Interactions

Beneficial Drug Combinations: Inhibit Metabolism penicillin antibiotic dehydropeptidase inhibitor renal dehydropeptidase https://en.wikipedia.org/wiki/Imipenem https://en.wikipedia.org/wiki/Cilastatin Metabolites

Beneficial Interactions

Condition PK Effects Metabolism inhibited Increased t1/2, Decreased CL Metabolism Induced Decreased t1/2, Increased CL

Condition PK Effects CL reduced C avg, ss, altered increased CL increased C avg, ss, altered decreased

Effect of Inhibitors fm = fraction down the metabolism route; CuI = concentration unbound inhibitor.

Effect of Inhibitors

NF-AT = nuclear factor activated T cell Cholesterol Lowering immunosuppressant NF-AT = nuclear factor activated T cell transcription factor

Effect of Inhibitors Cholesterol Lowering CYP2C9 substrate immunosuppressant CYP2C9 inhibitor https://en.wikipedia.org/wiki/Ciclosporin

Route of Administration https://en.wikipedia.org/wiki/Lovastatin https://en.wikipedia.org/wiki/Diltiazem CYP3A inhibitor Cholesterol Lowering Drug Calcium Channel Blocking Drug

Route of Administration https://en.wikipedia.org/wiki/Fluconazole https://en.wikipedia.org/wiki/Midazolam anti-fungal CYP3A inhibitor sedative

Mechanism-Based Inhibition

kobs = rate constant kinact observed kinact = rate of inactivation KI = inhibitory constant Y = [I]/(KI+[I]) http://www.nature.com/protocolexchange/protocols/1951 Remove Slide

Mechanism-Based Inhibition https://en.wikipedia.org/wiki/Clarithromycin

Mechanism-Based Inhibition + Clarithromycin + Clarithromycin https://en.wikipedia.org/wiki/Midazolam https://en.wikipedia.org/wiki/Clarithromycin Antibiotic Sedative

Induction anticoagulant anti-seizure/CYP 2C9 inducer https://en.wikipedia.org/wiki/Dicoumarol https://en.wikipedia.org/wiki/Phenobarbital anticoagulant anti-seizure/CYP 2C9 inducer

Multi-faceted Interactions Examples Displace protein binding and inhibit metabolism Compete with PD target and inhibit metabolism Displace protein binding and induce metabolism

Multi-faceted Interactions anti-coagulant Inhibition of Elimination https://en.wikipedia.org/wiki/Phenylbutazone https://en.wikipedia.org/wiki/Warfarin Phenylbutazone is AKA bute Phenylbutazone displaces Warfarin from Albumin The spike suggests that CYP NSAID Phenylbutazone Protein Binding Displacement Inhibit Elimination

Multi-faceted Interactions https://en.wikipedia.org/wiki/Quinidine https://en.wikipedia.org/wiki/Digoxin Na+/K+ ATPase Inhibitor Quinidine Displaces from tissues (Decreases V) Inhibits Pgp Na+/K+ ATPase Inhibitor

P-gp Inhibition Cause Effect increase intestinal absorption decrease biliary clearance decrease renal clearance Effect decreased biliary and renal clearance increased absorption rate (ka) increased AUC

Multi-faceted Interactions https://en.wikipedia.org/wiki/Rifampicin https://en.wikipedia.org/wiki/Atorvastatin Rifampicin is a CYP3A inducer. Rifampicin is a uptake transport inhibitor (OATP1B1 inhibitor) antibiotic CYP3A inducer/OATP1B1 inhibitor cholesterol lowering (Lipitor)

PD: Additive Effects Saturating A No A

Isobologram Isobologram- Equal concentrations across both axes; or IC50 Line on an Isobologram (Black, Red, Gray) = Isobole

mTOR = mammalian target of rapamycin a.k.a. rapamycin Cotylenin A mTOR = mammalian target of rapamycin gbL = positive regulator of rapamycin-sensitive pathway Raptor (RPTOR)= Regulator-associated protein of mTOR Bcl-2 = B-cell lymphoma 2 (inhibited) induce promote apoptosis reduce apoptosis (rapamycin) BAD (inhibited) p53 (activated) http://www.ncbi.nlm.nih.gov/pubmed/18754885 http://www.ncbi.nlm.nih.gov/pubmed/12718876 https://en.wikipedia.org/wiki/Bcl-2 https://en.wikipedia.org/wiki/RPTOR http://www.ncbi.nlm.nih.gov/pmc/articles/PMC60265/ Inhibits G1-S cell cycle progression http://www.jimmunol.org/content/178/4/2163.full.pdf

Isobologram Cotylenin A Rapamycin = Sirolimus https://openi.nlm.nih.gov/detailedresult.php?img=1410757_bcr1344-2&req=4 http://www.ncbi.nlm.nih.gov/pubmed/18754885 Rapamycin = Sirolimus