Module 4 Pharmacokinetics

absorption

distribution

metabolism

elimination

drug movement across cell barriers

diffusion

solute carrier/membrane transporter mediated processes

aqueous pores: 0.4nm; not for drugs

pinocytosis: very large molecules; vacuolization

lipid solubility

size: must not be too large

pH/ionization

partition coefficient: ratio of drug dissolution in oil/water

should be just lipophilic enough to pass through but not too lipophilic

crosses membrane when non-ionized

henderson-hasselbalch eq

basically pH - pKa = log(ratio of basic form to acidic form) for basic drugs the ionized form is the protonated/acid form BH+ for acidic drugs the ionized form is the basic form/deprotonated A-

ion trapping: ionization preference and retention of a drug in a compartment favoring it's ionization and dissolution

acidic drug compartmentalizes in high pH

basic drug compartmentalizes in low pH

aspirin ionization gastric juice < plasma < urine

pethidine/mepiridine ionization: gastric juice > plasma > urine

solute carriers (gradient dependent)

passive mvmt down gradients for a specific solute

structurally related organic cation transporter (OCT) and organic anion transporter (OAT)

OCTs

dopamine, choline, veruconium, quinine, procainamide

OCT2 : @ proximal calls in kidney, cisplatin (anti-cancer drug)

ATP-binding cassete (ABC) transporters

active transport against concentration gradients

P-glycoprotein transporters

responsible for drug resistances in cancer

@ high conc in intestine, renal tubular brush border membranes, and bile canaliculi

polymorphic variation

compartments

cytoplasm = chief reservoir for water soluble drugs, 35%

plasma = 5%

body fat = 20%

interstitial water = 16*

transcellular water = 2%

CSF

intraocular

peritoneal

pleural

synovial fluid

digestive secretion

volume of distribution

Vd= apparent volume of distribution; assumes drug is either in circulation or everywhere else in the body = volume of fluid req to contain the total amt D at the same conc as present in the plasma

D = dose; C0 = plasma conc at time zero

low Vd = primarily in the plasma

Blood Brain Barrier

no fenestrations = difficult solute passage

diffusion : highly lipophilic drugs

active transport

amino acids

glucose

amines

purines

locations

processes

primarily liver

Phase 1 : increase water solubility of drug: less able to be reabsorbed by the renal tubule

Phase 2 : alter structure to reduce intrinsic efficacy : aids in excretion

oxidation

addition of oxygen --> hydroxylation, oxidation, dealkylation or deamination = inc water solubility

reduction

hydrolysis

@ cytochrome system assoc = w/ ER; cytochrome p540 enzymes

conjugation of site chains to drugs; typically producing a polar molecule that is readily excreted

glucuronidation

sulphation

glutathione addition

glycine/water conjugation

methylation

first pass effect & pro drugs

first pass effect : absorption from small intestine direct to hepatic portal vein to liver = primary site of metabolism

lidocaine

pro-drugs : inactive drug precursor --> full drug activity afte metabolic processing; more active metabolites than original molecules

acetaminophen

Phase 1: cytochrome p450 enzymes : iron bearing heme proteins; superfamily w/ 74 gene families; net effect - addition of oxygen or hydroxyl

CYP1, CYP2, CYP3 = primary drug metabolizing enzymes

external regulation

grapefruit juice : CYP3A4 down regulated = inhibition of breakdown of some drugs by CYP3A4

brussel sprouts, cigarette smoke : induce p450 enzymes & increase drug breakdown

in plasma and other tissues

succinylcholine : metabolized by plasma cholinesterases

alcohol : metabolized by CYP2A6 in the liver and cytoplasmic alcohol dehydrogenase

examples

acetaminophen: NAPQI + glutathione

bilirubin and adrenal corticosteroids : glucuronidation = glucuronide formation: UDPGA = uridine diphosphate glucuronic acid --> transfer glucuronic acid to substrate

UDP-glucuronyl transferase

excretion

hepatic route

renal route (majority): pH and ionization dependent

from plasma to bile via SLC and P-gp transporters

enterohepatic circulation --> re-uptake excreted drugs

glomerular filtration

active tubular secretion

passive diffusion across tubular epithelium

smaller that mw 500-15000 readily pass and cleared

plasma protein bound drugs not filtered bc plasma proteins do not pass

via carriers (OAT, OCT)

highly lipophilic drugs or those non-ionized in urine

plasma clearance (Cl): volume of blood cleared of a drug through an organ per unit time; ml/min

feces, breath, sweat, saliva, tears, breast milk (minimal)

independent of kinetic parameters (Vd, bioavailability, drug half life) = constant

accounts for resorption and glomerular filtration

reduced clearance could indicate impaired kidney fxn or other excretory organ