Pharmacokinetics Module 3

intracellular water = aqueous cytoplasm =cheif reservoir for water soluble drugs (35%)

plasma water (5%), body fat (20%), interstitial water (16%) also are reservoirs

trans=cellular fluid (cerebrospinal, intraocular, peritoneal, pleural, synovial fluids, digestive secretions) = 2%

Volume of Distribution: Vd = D/C0

D = dose

C0 = plasma conc. at time 0

low Vd means drug is primarily in plasma (still in circulation)

high Vd means drug has left circulation

take blood sample to see if drug is in tissues or in circulation

Blood Brain Barrier

lacks fenestrations (small gaps that allow passage via diffusion)

for BBB cells must bass through 2 cell membranes so drugs/molecules exclusded

lipophilic drugs cross

AA, glucose, amines, purines are actively transported across BBB by carriers

increases free-drug conc. in plasma

equilibrium maintained as free drug goes into tissues and bound drug is released from proteins into free circulation

drugs can saturate binding sites on plasma proteins

drugs compete for binding to plasma proteins

depends on affinity

most drugs aren't bound in sufficient quantities to displace other drugs and drastically alter free concentrations

plasma proteins = albumin, lipoproteins, glycoproteins, beta globulins

saturation effect: doubling dose increases free conc. of drug in circulation as less drug reaches circulation and is instead bound by proteins. The unbound free drug is available for subsequent rxns.

Absorption: from site of administration

Distribution: w/in body to organs and tissues

Metabolism: biotransformation of drug; often inactivating

Excretion: removal of drug from body

Drugs cross membranes by passive movement or active transport

Diffusion = nonspecific (majority of drugs)

Specific carrier (majority of drugs)

SLCs/ABCs can transport drugs into and out of cells (influx and efflux)

Pinocytosis for large molecules

Small water soluble molecules go through aqueous pores

high level of lipid solubility = drug better able to interact/pass through lipid membrane

partial co-efficient: ratio of drug dissolving in oil/water

too much lipid solubility can = drug staying in membrane (not passing)

drug also needs to be able o pass through aqueous cell cytoplasm to enter blood, intestinal secretions, and urine

equal levels of ionization in oil/water

BH <--> B + H (for weak base)

EQ1: Ka = [B][H]/[BH] (dissociation constant)

EQ2: -logKa = -log[H] - log [B]/[BH]

EQ3: pKa = pH + log[BH]/[B]

most drugs = weak acids/bases that may be ionized or uncharged depending on pH of environment

ionized drugs dissolve well in aq fluids

uncharged forms pass through lipid membranes

knowing pKa of drug and pH of body fluid --> calculate proportion of drug ionized/how ready it crosses lipid membranes

pH-pKa = log[B]/[BH]

pH-pKa = log[A]/[HA]

THESE describe ionization state of drug at equilibrium

pH - pKa > 0

ionized

pH - pKa < 0

non-ionized

as pH increases relative to pKa of basic drug = nonionized and is lipid soluble

if pH is high relative to pKa of weak acid drug its more likely to be changed and less lipid soluble

Protonation of an acid make the molecule neutral

more likely to be absorbed [HA]

protonation of a base charges that molecule

more likely to be ionized/not absorbed [BH+]

weak acid (pKa 3.9) in acidic environment (pH 2) is nonionized

pH=pKa < 0

greater lipid solubility

weak acid (pKa 3.9) in more basic environment (pH 8) is ionized

pH-pKa >0

readily dissolves

pH favoring non-ionized form = more likely to pass from aq compartment

pH favoring ionization = accumulation in compartment

ion trapping: drug in compartment favoring its ionization/dissolution

acidic drug accumulates in compartment with high pH

basic drug accumulates in compartment with low pH

BUT diffusion at eq. means fractions of non-ionized drugs can be found in compartments of varying pH

Liver = main site for drug metabolism

makes it more water soluble/less re-absorbed by renal tubule

alters structure to reduce its intrinsic efficacy

first pass effect = metabolize drugs before reaching circulation

in gastric mucosa or after absorption from gut into hepatic portal vein (in liver)

reduces bioavailability of drug before reaching systemic circulation

metabolic activity also makes metabolites more active than original molecules (pro-drugs)

can also produce metabolites more active AND more toxic than parent drug

Subtopic

Phase 1 Metabolism: oxidation runs, reduction and hydrolysis

adds reactive residue to processed molecule

oxidation adds O = hydroxylation, oxidation, dealkylation, deamination - increase water solubility

mediated by cytochrome system (P450NZ)

cytochromes (hepatic cytoplasmic microsomal drug metabolizing NZs) are in the liver

iron bearing haem proteins (CYP1/2/3)

genetic variations in p450 NZs = variation in response to drugs

p450 can be regulated by external factors (grapefruit juice, smoke)

not all drug oxidation is cytochrome liver system

INSTEAD: can occur in plasma or other tissues

Phase 2 Metabolism: conjugation of side chains to drugs

through glucuronidation, sulphation, glutathione addition, methylation, glycine addition, and water conjugation

produces polar molecule that can be excreted

mainly take place in liver; but also lung/kidney

can conjugate to residue created by phase 1 rxns

normally result in inactive product

Hepatic route

drugs/substances transported from plasma to bile via SLC and P-gp transporters

Enterohepatic circulation can re-uptake excreted drugs

losing conjugate through hydrolysis = reactivation of drug and reabsorption by body

results in prolonged drug action

Renal route

glomerular filtration

molecules smaller than 5000-15000 can pass

plasma proteins (albumin) don't pass bc too large

plasma protein bound drugs aren't filtered

**warfarin is 98% bound to albumin (2% avail for filtration)

active tubular secretion

involves specific transport carriers (OAT, OCT)

can be antagonized

passive diffusion across tubular epithelium

lipophilic drugs and those non-ionized in urine can be reabsorbed

pH of urine can vary due to diet and drug intake

ion trapping increases drug retention in the urine

weak acids excreted less in acidic urine

weak acids excreted more in alkaline urine

99% water filtered is reabsorbed long tubule, thus drugs are reabsorbed due to concurrent resorption of water

lipophilic drugs cross membranes easier and are reabsorbed more than polar hydrophilic molecules

also excreted via feces, breath, sweat, saliva, tears, breast milk

Plasma Clearance: volume of plasma cleared of drug/unit time (ml/min)

clearance is constant for a drug since volume of distribution, bioavailability and drug half life are constant

measure of efficiency of organs of elimination (wellness of patient)

reduced clearance = impairment of excretory organ

Drug elimination: measure of loss of drug mass from circulation/unit time (mg drug/hour)

includes loss of drug by metabolism and excretory routes

total body clearance: sum of all clearances by various mechanisms

mediate cell uptake/movement across membrans

Solute Carriers (SLC)

Passive movement of solutes down gradients

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

transports single species in direction of its electrochemical gradient

facilitated diffusion

ATP-binding transporters

transport against concentration gradients

P-glycoproteins (P-gp)

responsible for drug resistance in cancer (mediate removal of drugs from cells)