pharmacokinetics - laulima...a"beale" phrm203"."pharmacokine7cs" 3...

Pharmacokinetics What the body does to the drug

Allison Beale PHRM 203

A Beale PHRM 203 -‐ Pharmacokine7cs 2

Pharmacokine7cs What the body does to the drug

•  Applies to all drugs – Absorp7on – Distribu7on – Metabolism – Excre7on

Medical considera4ons:

Assess the pa4ent’s ability to process drug (e.g., pre-‐exis4ng diseases) and determine if exis4ng prescrip4ons are incompa4ble.

Monitor for effec4veness/toxicity.

Teach proper self-‐administra4on techniques and alert pa4ent about incompa4bili4es. ADME


ADME “Givens”

•  The drug must enter body to be ABSORBED

•  It must cross barriers to enter the body, blood or lymph & be DISTRIBUTED

•  If it is metabolized, it will undergo METABOLISM via the same processes as food materials

•  It will be EXCRETED


ADME: Processes of absorp4on •  Passive diffusion –  Through gaps between cells or through cells-‐ depends on: •  Surface area •  Diffusion gradient •  Diffusion coefficient •  Solubility factors

–  Types of Passive Diffusion •  Lipid diffusion •  Aqueous diffusion

• Ac7ve transport – Through pores or channels – Specific and can be saturated •  Facilitated diffusion –  Pores for small molecules

•  Carrier mediated –  P-‐Glycoprotein pumps – Organic anion-‐transpor7ng polypep7de (OATP)

– Mul7-‐drug resistance proteins (MRP)

•  Endocytosis –  For “solids” or large substances like Vit B12 complex

•  Pinocytosis –  For liquids or dissolved substances


ADME Barriers to absorp4on

–  Drug Formula4on •  e.g., lipid soluble, water soluble, ionized •  Size of drug (small passes through barriers easier than big)

–  Epithelial Membranes •  Skin, gut, lungs, blood vessels

–  Enzymes •  In gut and other 7ssues, including bacteria in those 7ssues

–  Presence/absence of transport system •  Efflux & Uptake Pumps

–  P-‐glycoprotein (p-‐GP) and other ABC Transporters –  Organic anion transpor7ng pep7de (OATP), etc.


ADME: Factors affec4ng PO absorp4on

–  Drug Formula4on •  Disintegra4on of drug formula7on

–  Chemical stability of drug •  Various pH’s •  To GI & gut flora enzymes •  To other drugs

– Mo4lity and mixing of GI contents •  Gastric emptying 7me and eme4c effects •  Presence and type of food or other drugs

–  GI, liver, cardiac, or kidney disease •  Condi4on of GI wall (edema?) •  Blood flow to GI tract


ADME: Bioavailability The propor7on of the drug that is absorbed & makes it

to the site of ac4on (afer metabolism) •  IV results in (essen7ally) 100% bioavailability •  IM & SC next -‐ then Inhala7on (some lung 1st pass) •  Then PO (lots of metabolism in GIT and in liver – 1st pass) •  Other routes:

–  Topical formula7ons are locally ac7ve •  Not much actually gets into the blood stream

–  Transdermals •  Formulated to penetrate skin bypassing 1st pass effect, stomach acid and other PO

variables. –  Rectal

•  Important for unconscious and vomi7ng pa7ents •  50% bypasses liver 1st pass, but uptake is unpredictable


ADME: Variables affec4ng distribu4on

– Drug Formula4on •  Solubility, ioniza7on

– Plasma protein and 4ssue binding •  Plasma proteins

–  Albumin for acids, α1 acid glycoprotein for bases, etc. •  Tissue proteins, phospholipids, nucleic acids etc.

– Cardiac output and 7ssue perfusion – Drug molecule size

•  Large molecules stay in blood vessel longer – Extent and type of metabolism

•  1st Pass Effect, gut flora, gut enzymes, acids, etc.


ADME: Volume of Distribu4on Vd The volume of fluid needed to dissolve a drug and achieve the same

concentra7on as in plasma.

–  It is not representa7ve of any actual body compartment –  It is a measure of the dose versus the plasma concentra7on

–  Increased by •  Plasma protein binding (PPB) and 7ssue sequestra7on •  Ion trapping •  Kidney and/or liver disease

–  Decreased by •  Dehydra7on, age, body composi7on changes

Fat as reservoir Obese ≥50% fat Normal ~25% Very lean ~10%

↑ % fat, ↑’s Vd & t 1/2 of lipid soluble drugs (e.g., diazepam, thiopental, trazodone….)


Volume of Distribu4on con4nued

•  Volumes of various compartments: – Plasma 3.5 liters or 0.92 gallons – Extracellular fluid 14 liters or 3.7 gallons – Total body water 40 liters or 10.5 gallons

•  Infants <1 yr. = 75-‐80% body wt. = TBW •  Adult male = 60% •  Adult female = 55%

Be aware of changes in the Vd of water soluble drugs like lithium, digoxin, alcohol, and aminoglycoside an7bio7cs

↓ total body water due to ↓ muscle mass &/or ↑ body fat


ADME: Volume of Distribu4on, con4nued –  ION TRAPPING

•  Example: Weak bases

•  They are LESS ionized in PLASMA than when inside the cell because the cell pH is LOWER. The lower (more acidic) pH causes the weak base to ionize and it can’t cross back through the plasma membrane

•  Thus bases are trapped inside cells & lysosomes (or on the acidic side of a membrane) -‐ the opposite occurs with acids

•  Important applica7ons –  This is why most oral drugs are weak bases –  Change urine pH to improve renal excre7on (of drug from blood)

Weak Bases trapped by • fetus (anestheBcs, most oral drugs) • stomach (most oral drugs)

Weak Acids trapped by • intesBnes (NSAIDs)


Effects of plasma and 7ssue protein binding

•  Tissue binding –  Proteins, phospholipids, nuclear proteins –  ↑ [drug]7ssue

•  Renal toxicity with aminoglycosides

•  Albumin –  Binds mostly acids including bile acids –  Sulfonamides displace bile acids from albumin

•  Bilirubin encephalopathy in newborns •  α1 acid glycoprotein (α1-‐AG)

–  Binds mostly basic drugs –  Cancer, arthri7s, MI, Crohn’s disease all trigger acute-‐phase

inflammatory response and α1-‐AG synthesis •  Decreased effec7veness of basic drugs

Plasma Proteins (PP) synthesized in the liver,

except for IGs •  60% albumins •  35% immunoglobulins •  4% fibrinogen &

prothrombin •  Enzymes, regulatory

proteins, lipoproteins, transferrin, hormones

An example of when

PPB may be important


ADME: Biotransforma4on •  Processes –  Phase I -‐ REDOX –  Phase II -‐ Conjuga7on

•  Loca7ons –  Liver (primarily) –  Kidney –  Lung –  GI –  Plasma –  Other Tissues

Pre-existing liver and/or kidney disease make it more likely someone will have

complications with any given medication

Exis7ng enzyma7c pathways for food & contaminants naturally occurring in food (e.g., plant-‐derived toxicants) Subject to limita7ons of enzyme-‐based systems

Induc7on/Inhibi7on Compe77on Specificity Gene7cs & individual variables First Pass Effect


ADME: Phase 1 reac4ons (Redox)

Phase I -‐  Smooth endoplasmic re7culum (SER) Cytochrome P450 dependent enzymes -‐  Oxida7on -‐  Reduc7on -‐  Hydrolysis

-‐  Goals -‐  ↑Water solubility -‐  To create sites for Phase II

reac7ons (Conjuga7on)

•  Cytochrome = colored (red, due to iron)

•  P450 = wavelength of light absorbed by the enzyme when exposed to CO.

•  Many (many) isoforms, 6 well studied

•  Nomenclature: e.g., isoform CYP2D6 –  CYP = cytochrome P450

enzyme –  2 = Family (there are 4) –  D = Gene7c Sub family (6, A-‐F) –  6 = Specific gene, perhaps 20

isoenzymes? -‐ note the nomenclature is gene7cally based, not FUNCTIONALLY


Note: P450 metabolism slows to 50-‐75% of peak afer 65 years of age


General Biotransforma7on

www.medscape.com/pi/editorial/clinupdates/2000/301/art-‐cm.drug.fig3.gif

Phase 2 Phase 1


ADME: Consequences of metabolism

•  Inac4ve products •  Ac4ve metabolites •  Similar, but different to parent drug • More ac4ve than parent • New ac4on •  Toxic metabolite


ADME: Variables affec4ng biotransforma4on

•  Metabolism affected by: – Which pathways are available

•  Biotransforma7on occurs via established enzyma7c pathways. •  It may increase, decrease or alter drug availability/ac7ons.

–  Individual variables of age, sex, size/weight, diet, race and other gene7c factors, compliance with dosing schedule, pregnancy, species, disease

–  Interac7on with other drugs –  Enzyme altera7ons -‐ inhibi7on, induc7on of paths –  Environmental factors (e.g., SMOKING) –  Drug related factors -‐ dose, formula7on


ADME variables: Age •  Very young –  High surface area to volume ra7o –  Not metabolically “competent”

•  Chloramphenicol → “grey” baby syndrome –  Almost no Phase 2 enzymes, so can’t glucuronidate

•  Fetus poor overall metabolism –  CYP3A subfamily of Phase 1 enzymes only

•  Very old –  Diminished proteins

•  ↓metabolism and excre7on •  Altered Vd (less muscle mass…)

–  Reduced kidney func7on –  Average 10 drugs/pa7ent in care facili7es


ADME variables: Disease •  Liver

–  Δ’s in metabolism, plasma proteins, excre7on…

•  Kidney –  Δ’s in filtra7on, secre7on, re-‐absorp7on, metabolism…

•  GI –  Vomi7ng, diarrhea, Δ’s in metabolism, gut flora…

•  Cardiac –  Δ’s in perfusion…

•  Diet –  Malnutri7on, mono-‐diet, nutrient deficiency(ies) -‐ Δ’s in Vd,

plasma proteins, absorp7on, distribu7on, metabolism


ADME variables: Pregnancy

•  Placenta HIGH in CYP1A in smokers – ⇑ risk teratogenicity – ⇑ risk carcinogenicity – ⇑ risk hepatotoxicity

•  Profound induc7on of P450s in mom –  Issues like altering an7convulsant dose (will need a lot more)

•  Fetus is more acidic than mom –  Ion trapping basic drugs

Estradiol maintains pregnancy and is a CYP1A

substrate* - metabolism yields carcinogen in smokers

* Division of Clinical Pharmacology, Indiana State

University Department of Medicine, P450 Drug

Interaction Tables: Clinically Relevant Table


ADME variables: First Pass •  PO Drug metabolized by enzymes: – Gut (both endogenous and bacterial enzymes) – Liver •  Portal vein goes from GI directly to liver (1st pass)

•  Results in poor oral bioavailability – Propanolol 26% oral bioavailability •  Big 1st pass losses •  Beta blocker an7anginal, an7arrhythmic, anxioly7c…

– Aztreonam ~0% oral bioavailability •  Monobactam (beta lactam) an7bio7c

Therapeu4c considera4on: use another formula4on/route?


ADME: Phase I drug interac4ons

•  Inhibitors of microsomal enzymes – Prolong the ac7on of drugs metabolized by those enzymes g toxicity

–  Inhibit pro-‐drugs from being biotransformed into ac7ve agent g treatment failure

•  Inducers – Shorten the ac7on of drugs g treatment failure –  Increase the effects of pro-‐drugs g toxicity


ADME: CYP3A modifiers (FDA) •  Inhibitors –  Azole an7fungals

•  Ketoconazole •  Itraconazole •  Fluconazole

–  Cime7dine – Macrolide an7bio7cs

•  Clarithromycin •  Erythromycin •  Troleandomycin

–  GRAPEFRUIT JUICE

•  Inducers –  Carbamazepine –  An7-‐TB drugs

•  Rifampin •  Rifabu7n

–  An7retrovirals •  Protease Inhibitors like Ritonavir

•  Non-‐Nucleoside Reverse Transcriptase Inhibitors

–  ST. JOHN’S WORT

Some drugs metabolized by CYP3A:

HIV an4virals (PI’s), birth control pills, TCAs & cyclosporine

We cover blue drugs


CYP3A4 substrates that are poten7ally N toxic N when combined with inhibitors

•  Alfuzosin •  Alprazolam •  Budesonide •  Carbamazepine •  Colchicine •  Cyclosporine •  Dexamethasone •  Disopyramide •  Ergotamine •  Flu7casone •  Lovasta7n •  Methylprednisolone

•  Midazolam •  Pimozide •  Quinidine •  Repaglinide •  Rifabu7n •  Sildenafil •  Simvasta7n •  Tadalafil •  Triazolam •  Vardenafil •  Vinblas7ne •  Vincris7ne

We cover red drugs


ADME: CYP1A2 Induced by Smoking

•  Substrates: –  Theophylline –  Imipramine –  Propranolol –  Clozapine –  Estradiol

•  INHIBITED BY: – Many fluoroquinolone an7bio7cs

–  Fluvoxamine –  Cime7dine

www.fda.gov/cder/drug/drugReac7ons/

We cover red drugs


Gene7c variability www.m

edicine.iupu

i.edu

/flockhart/2C

19_P

M.jp

g 2C19 substrates include: omeprazole,

diazepam, phenytoin, amitriptyline, clopidogrel, cyclophosphamide, progesterone


Gene7c variability example

•  2D6 – 8-‐10% Caucasians = poor metabolizers • Affects SSRIs, TCAs, Opiates (e.g., codeine) • Analgesic effect of codeine depends on metabolism (by CYP2D6) to morphine – Some people have a duplicate copy(ies) of the gene coding for 2D6 » Strong reac7on to codeine

– Poor metabolizers may have li|le reac7on


ADME: Phase II reac4ons (conjuga4ons)

– Microsomes or cytosolic – Common Conjuga4on reac7ons

•  Acetyla7on •  Amina7on •  Glucuronida3on •  Glutathione conjuga7on •  Methyla7on •  Sulfa7on

–  Cofactor: 3'-‐phosphoadenosine-‐5'-‐phosphosulfate (PAPS) – Excre7on into bile or urine

•  May improve water solubility or not


Major Conjuga7on Reac7ons: enzymes & func4onal groups

Reaction Enzyme Functional groups

Acetylation N-acetyl transferases -NH2 -SO2NH2

-OH

Glucuronidation UDP-glucuronosyltransferases

-OH -COOH

-NH2 -SH

Glutathione Glutathione S-transferases

Epoxides Organic halides

Methylation Thiopurine methyl transferases -OH

-NH2 -SH

Sulfation Sulfotransferases -NH2 -SO2NH2

-OH


ADME: Phase II Glucuronida4on

•  Major mammalian Phase II pathway – Inducers include: • Phenobarbital, cigare|e smoking

– Substrates include: • Methadone, morphine, valproic acid, NSAIDS, bilirubin, steroid hormones

We cover red drugs


ADME: Phase II RXNS -‐ gene4c differences in Acetyla4on

•  Rapid and slow acetylators – Various muta7ons alter enzyme ac7vity or stability

–  Incidence of slow acetylators •  70% in Middle Eastern popula7ons; 50% in Caucasians; 5-‐25% in Asians

– Drug toxici4es in slow acetylators •  Nerve damage from dapsone •  Bladder cancer in cigare|e smokers due to increased levels of hydroxylamines

– Treatment failure in rapid acetylators


ADME: Other non-‐microsomal rxns •  Hydrolysis ✴

–  Plasma (esterases) –  Esterases

•  Alcohol & aldehyde dehydrogenase in cytosolic frac7on of liver ✴ –  e.g., ethanol

•  Monoamine Oxidases (MAOs) ✴ –  Mitochondria, e.g., dopamine and catacholamines (NE, EPI)

•  Catechol-‐O-‐methyl Transferase (COMT) •  Xanthene oxidase ✴

–  Mostly in kidneys -‐ uric acid produc7on •  Other enzymes for specific drugs -‐ tyrosine hydroxylase

✴ Also Phase 1 reac4ons, not all Phase 1 rxns are P-‐450


ADME: Routes of excre4on •  Kidney

–  Urine, water soluble drugs and conjugates •  Liver

–  Bile, lipid soluble & large (>300 MW), polar drugs & conjugates

•  Lungs –  Vola7le inhala7on anesthe7cs

•  Other secre7ons –  Skin

•  Sweat, insignificant (except when PROFUSELY swea7ng) –  Tears

•  Insignificant –  Milk

•  Generally insignificant, with excep7ons


Variables affec4ng renal excre4on

•  Drug/metabolite characteris4cs -‐ solubility, ioniza7on, dose/dura7on

•  Disease -‐ especially renal or hepa7c •  Poor cardiac output/renal perfusion •  Plasma protein binding •  Drug interac4ons –  Aspirin and Probenecid ⊗ tubular secre7on –  BUT – they interfere with the ac7vity of each other!


Renal excre4on •  Glomerular filtra7on (into urine)

–  Kidney blood flow ~ 650 ml/min, ~20% filtered •  130 ml/min = GFR

–  GFR ↓ in newborns, elderly, kidney and heart disease –  If GFR ↓’d, then, ↓ dosage and/or ↑ dosing interval

•  Passive and ac7ve re-‐absorp7on (back into blood) –  Diffusion or ac7ve transport for CBHs, aa.s, vitamins, etc.

•  Tubular secre7on (into urine) –  Two separate, ac7ve processes for acids/bases –  PPB drugs rapidly dissociate as the free drug is secreted –  Inhibited by probenecid (Benuryl) ! and aspirin !

The ! symbol indicates something you should know about a drug we

cover. Later you will see tables of

info headed by the ! symbol.


Drugs excreted by a carrier mediated process in the proximal tubule (tubular secre4on)

•  Acids –  Penicillin G –  Ampicillin –  Sulfisoxasole –  Phenylbutazone –  Furosemide –  Probenecid –  Glucuronic acid conjugates

–  Aspirin

•  Bases –  Procainamide –  Dopamine –  Neos7gmine –  Trimethoprim

To ↑ excre4on of acids give sodium bicarbonate (NaHCO3).

We cover red & blue drugs


Extrac4on ra4os for drugs excreted >30% in urine (ER = 1 → a drug is completely removed aker 1 passage)

Low (<0.2) Intermediate High

Acetazolamide Diazoxide Digoxin

Furosemide Gentamicin Kanamycin

Phenobarbital Sulfasoxazole Tetracycline

Procainamide Quaternary ammonia

compounds

Many: Penicillins

Glucuronides Sulfates

Glycine conjugates (Phase 2 products)


Renal drug clearance

•  Lower in: – Elderly and newborns – Women (20% less than men) – Kidney and heart disease pa7ents – Pa7ents taking secre7on blockers

•  Aspirin and probenecid •  In pa7ents with lowered renal drug clearance: Lower the DOSE

Renal function ↓ 1%/year

during adulthood


Hepa7c Drug Clearance

•  Drugs with high extrac7on ra7o – E.g., Propranolol, lidocaine and morphine – Significant 1st pass – Clearance determined by blood flow, not metabolism •  Lower in the elderly, liver and heart disease

– Lower blood flow – Lower metabolism


Hepa7c Drug Clearance 2

•  Drugs with low extrac7on ra7o – Tolbutamide, warfarin, phenobarbital – 1st pass not significant – Clearance regulated by metabolism, not blood flow

– Clearance reduced in newborns, elderly, liver disease, malnourished/alcoholics •  Lowered metabolic ability


Hepa7c Drug Clearance

•  Secre4on into bile – Bile acids synthesized from cholesterol – Drugs secreted include acids, bases, estrogen (steroids), metals

– Variables affected by liver disease •  Bile flow ↓ (cholestasis) •  Drug metabolism and clearance ↓ •  Bilirubin clearance ↓ (jaundice) •  Bile acid clearance ↓ •  Plasma protein synthesis ↓

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