pharmacokinetic interactions: a mechanistic approach part 1 · 2015-03-19 · • results in...
TRANSCRIPT
![Page 1: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/1.jpg)
Pharmacokinetic Interactions: A Mechanistic
ApproachPart 1
Barry E. Gidal, PharmD
![Page 2: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/2.jpg)
Pharmacokinetic Interactions
• Absorption– Adsorption– Intestinal Metabolism– Transporters
• Distribution– Protein Binding – Transporters
• Elimination– Renal Excretion– Hepatic Metabolism
![Page 3: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/3.jpg)
Human Drug Metabolism
Gut &Liver
Conjugation
Glucuronidation
NADPH-dependentCYP450 reductase
Oxidation
Cytochrome P450
Sulfation
![Page 4: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/4.jpg)
Absorption
![Page 5: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/5.jpg)
Absorption Interactions
• Adsorption: – Bioavailability
![Page 6: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/6.jpg)
Absorption Interactions
• Adsorption: – Bioavailability– Antacids can decrease the rate and/or extent of absorption
– Need to separate out administration of antacid and drug by at least 2 hours.
• atenolol ciprofloxacin enoxacin isoniazid ketoconazole norfloxacin ofloxacin tetracycline
![Page 7: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/7.jpg)
Absorption Interactions:Food effect
• Large number of drugs whose absorption may be affected by food
• Food can cause adsorption and/or delayed gastric emptying
• Results – Increased and/or accelerated absorption – Decreased and/or delayed absorption
» Singh et al. Clin Pharmacok 1999;37:213‐255
![Page 8: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/8.jpg)
Absorption: Intestinal Metabolism
• Highest concentration of enzymes is upper small intestine – duodenum and jejunum > ileum and colon
• CYP3A4 – primary isozyme in GI– 10‐50% lower than in liver– Drugs with significantly intestinal metabolism
• Cyclosporine Midazolam Cisapride• Tacrolimus Nifedipine Terfenadine• Saquinavir Felodipine Simvastin• Indinavir Nisoldipine Lovastatin
![Page 9: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/9.jpg)
Absorption: Intestinal Metabolism and Drug Interactions.
• Inhibitors of CYP3A4– Ketoconazole Itraconazole– Erythromycin Verapamil– Grapefruit Juice
• Inducers of CYP3A4– Phenytoin Carbamazepine Rifampin – St Johns Wort
![Page 10: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/10.jpg)
Transporters Proteins
• Role of transport proteins in absorption, distribution and excretion
• Control distribution of drugs across membranes• Extent of initial membrane permeability is affected by the physiochemical properties of the drug.
• Transport proteins can play a key role in extrusion of drugs from organs and altering drug absorption, brain penetration, renal and hepatic elimination
• Drug interactions affecting induction and inhibition of the transporters
![Page 11: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/11.jpg)
Transporters
• P‐glycoprotein (PgP)• Multi‐drug resistance (MDR)• Organic Anion Transporter (OAT)• Organic Cation Transporter (OCT)
» Ayrton and Morgan Xenobiotic 2001;31:469‐497
![Page 12: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/12.jpg)
P‐Glycoprotein:History
• Clinical oncologists first to recognize multi‐drug resistance– Cross resistance to other cytotoxic agents
• First detected in early 1970’s in cultured cells selected for MDR
• Subsequently cloned from mouse and human cells
• Now one of the most extensively studied members of the ABC superfamily
![Page 13: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/13.jpg)
P‐Glycoprotein
![Page 14: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/14.jpg)
Physiological Significance of Pgp
• Drug absorption, distribution, and elimination
• Cytotoxic protection mechanism
• Cell volume regulation by chloride transport
• Steroid transport
• Peptide transport
![Page 15: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/15.jpg)
P‐glycoprotein in Normal Tissues
On the apical surface• Intestine (jejunum, ileum, colon)• Liver• Blood brain barrier• Kidney• Testis• Adrenal cortex• Leukocytes and stem cells
– NK cells, CD4+, CD8+, and bone marrow progenitor cells• Placenta
![Page 16: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/16.jpg)
Absorption: Transporters
• P‐glycoprotein (PgP)– Transmembrane Protein– Function as cellular efflux pumps
• Results in absorption of drugs
– Distributed throughout the body• Intestinal lumen, liver, kidney, blood brain barrier
– Inducible– Close proximity to CYP3A4 with significant substrate overlap
• can act synergistically to limit bioavailability of drugs
![Page 17: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/17.jpg)
CYP3A and P‐gps work together in the gut
• Many substrates of P‐gps are also CYP3A4 substrates
• In small intestine, P‐gps efflux compound to lumen, then compound is reabsorbed; this “shuttle” leads to increased “exposure” of compounds to CYP3A4 and maximizes their activity
![Page 18: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/18.jpg)
pgp
pgp
pgp
drug
drug
drug
3A4
3A4
3A4
P-gps in “front”- with repeated shuttles of absorption/efflux
Intestinal Cells
![Page 19: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/19.jpg)
Transporter Interactions• Interactions
– Induction• Rifampin• St. John’s Wort• Garlic
– Inhibition• Verapamil Diltiazem Nifedipine Felodipine• Clarithromycin Erythromycin Itraconazole Ketoconazole• Cyclosporine Tacrolimus• Quinidine Amiodarone Talinolol• Tamoxifen• Testosterone
![Page 20: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/20.jpg)
Distribution
![Page 21: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/21.jpg)
Pharmacokinetic Interactions ‐Distribution
• Distribution– Protein Binding interactions
• Total blood concentrations no longer reflect unbound drug concentrations.
• Only effects – a small number of highly protein bound drugs– that are monitored by total blood concentrations.
![Page 22: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/22.jpg)
Distribution: Transporter Interactions
• P‐glycoprotein limits the penetration of a drugs across the blood brain barrier.
• Administration of a PgP inhibitor has the potential to increase drug delivery to the brain
![Page 23: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/23.jpg)
Distribution: Transporter Interactions
• Loperamide (PgP substrate) is a potent opiate that reduces GI motility; however it has no centrally mediate opiate effects (respiratory depression) alone.
• Loperamide + quinidine (a PgP inhibitor) – resulted in respiratory depression– Not explained by increased loperamide plasma concentrations
• Sadeque et al. CPT 2000;68:231‐7.
![Page 24: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/24.jpg)
Metabolism
![Page 25: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/25.jpg)
Cytochrome P‐450
• A group of enzymes with are located on the endoplasmic reticulum. These enzymes are of particular importance when studying drug
biotransformation and drug metabolism.
• It is known that the gene for cytochrome P-450 has existed for more then 3.5 billion years. This indicates drug metabolism by the P-450
system is a new and secondary role for these enzyme systems.
• The primary role for the P450 system seems to be one of metabolism and detoxification of endogenous compounds after they have been
taken in by mouth.
• This accounts for the high concentrations of these enzymes located in the liver and small intestine.
![Page 26: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/26.jpg)
Hepatic Drug Metabolism
2B71A91A41A33A42D62C192C92E11A2
CYP450 UGT
Cloyd, J 2000
![Page 27: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/27.jpg)
A. di Masi et al. Molecular Aspects Medicine2009;30:297-343
![Page 28: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/28.jpg)
Relative Levels of P450 isozymes in human liver
30%
20%2%
13%
7%
28%CYP 3A4CYP2CCYP2D6CYP1A2CYP2E1Other
Shimda et al. JPET 1994;270:414-423Wrighton & Stevens Crit Rev Tox 1992;22:1-21
![Page 29: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/29.jpg)
Meyer RP, et al. Current Drug Metabolism 2007;8:297-306
CYP’s: More Than Systemic Drug Clearance:Distribution of Brain CYP 450
![Page 30: Pharmacokinetic Interactions: A Mechanistic Approach Part 1 · 2015-03-19 · • Results in absorption of drugs – Distributed throughout the body • Intestinal lumen, liver, kidney,](https://reader030.vdocuments.us/reader030/viewer/2022041001/5ea11d5e9c4b507cc97df12a/html5/thumbnails/30.jpg)
End of Part 1