Pharmacokinetic Interactions: A Mechanistic 

ApproachPart 1 

Barry E. Gidal, PharmD

Pharmacokinetic Interactions

• Absorption– Adsorption– Intestinal Metabolism– Transporters

• Distribution– Protein Binding – Transporters 

• Elimination– Renal Excretion– Hepatic Metabolism

Human Drug Metabolism

Gut &Liver

Conjugation

Glucuronidation

NADPH-dependentCYP450 reductase

Oxidation

Cytochrome P450

Sulfation

Absorption

Absorption Interactions

• Adsorption:  – Bioavailability

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 

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

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

Absorption: Intestinal Metabolism and Drug Interactions.

• Inhibitors of CYP3A4– Ketoconazole   Itraconazole– Erythromycin   Verapamil– Grapefruit Juice

• Inducers of CYP3A4– Phenytoin  Carbamazepine  Rifampin  – St Johns Wort   

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

Transporters

• P‐glycoprotein  (PgP)• Multi‐drug resistance  (MDR)• Organic Anion Transporter (OAT)• Organic Cation Transporter (OCT)

» Ayrton and Morgan   Xenobiotic 2001;31:469‐497

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

P‐Glycoprotein

Physiological Significance of Pgp

• Drug absorption, distribution, and elimination

• Cytotoxic protection mechanism

• Cell volume regulation by chloride transport

• Steroid transport

• Peptide transport

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

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

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

pgp

pgp

pgp

drug

drug

drug

3A4

3A4

3A4

P-gps in “front”- with repeated shuttles of absorption/efflux

Intestinal Cells

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

Distribution

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.

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

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.

Metabolism

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.

Hepatic Drug Metabolism

2B71A91A41A33A42D62C192C92E11A2

CYP450 UGT

Cloyd, J 2000

A. di Masi et al. Molecular Aspects Medicine2009;30:297-343

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

Meyer RP, et al. Current Drug Metabolism 2007;8:297-306

CYP’s: More Than Systemic Drug Clearance:Distribution of Brain CYP 450

End of Part 1