Elimination

General Principles

elimination depends on: (1) chemical properties of drug (2) what kind of barriers it has to cross

orally administered drugs must have some lipid solubility to be absorbed in GI; otherwise, eliminated in feces

lipid solubility is often a function of pK_a of the drug and the pH of the stomach

once in body, most drugs eliminated by kidney, sometimes after metabolism by the liver (water soluble)

liver can eliminate drugs (either metabolized or unchanged) in the bile (lipid soluble)

if subsequently reabsorbed can lead to enteric circulation of drug (confused with slow elimination)

properties of most drugs:

low MW (<20k); usually either WOA or WOB (have charged and uncharged forms)

charged forms (water soluble) can penetrate dialyzing membranes: capillaries; glomeruli

Þ rapid elimination by kidney

lipid soluble forms penetrate selectively permeable barriers: GI, blood-brain, cells

Þ slow elimination by the kidney; liver may convert to more water soluble metabolite

Renal Elimination

70kg man: RBF = 25% of CO (1.3L/min); RPF = 50% of RBF (650 mL/min); GFR = 20% of RPF (130 mL/min)

Þ 99% of filtrate must be reabsorbed

clearance (= elimination/concentration): volume of fluid from which all drug is removed per unit time; fraction of drug eliminated per unit time

since kidney and liver are major elimination routes usually broken down to:

Cl_total= Cl_kidney + Cl_hepatic + Cl_other (Cl_O may include lungs in case of volatile (gaseous) drugs)

Cl_T and Cl_R can be estimated from C_plasma vs. time and rate of excretion in urine respectively

rate of excretion in urine = (volume of urine x urine concentration) / time Þ mg/min

renal clearance = (mg of drug excreted in urine per min) / (mg drug per mL in plasma) Þ mL/min

(in other words, = (rate of excretion) / (plasma concentration))

rate of elimination = clearance x (blood/plasma concentration) Þ mg/min

Cl_O usually negligible

elimination is usually first order

constant fraction of drug eliminated per unit time; logCl vs. time Þ straight line

if truly first order, clearance is independent of drug concentration in circulating fluid, but elimination is dependent

clearance of inulin estimates GFR

must distinguish clearance from rate of elimination from body (T_1/2)

T_1/2 = (0.693 x V_D) / Cl Þ elimination from body is dependant on both V_D and Cl

glomerular filtration

passive through dialyzing membrane

proportional to RPF, integrity of glomerulus, concentration of unbound drug

WOA bind to albumin; WOB bind to alpha acid proteins

Þ filtration rate = GFR x drug concentration in plasma x fraction of free drug

active tubular secretion

energy dependant, efficient, saturable

can remove drugs bound to plasma through active transport and mass-action principle

binding to plasma proteins may even accelerate elimination

Þ binding in plasma reduces V_D, sequesters drug in plasma

separate systems exist for anions and cations

both systems have wide specificity, many substances could potentially compete but the concentrations of drugs are normally so low anyway that this is not a problem

maximum clearance through tubular secretion is RBF (~650 mL/min) » PAH

secreted WOA: PAH, probenecid, penicillins, cephalosporins, thiazide diuretics, NSAIDS, glucuronide and sulfate conjugates, lactate, urate

secreted WOB: TEA, amiloride, morphine, quinine, creatinine, procainaminde

secretion of organic anions (PAH system) – weak organic acid; proximal renal tubular epithelium

basolateral membrane: PAH/a -KG exchanger (in/out); Na/a -KG cotransporter (in/in); NaKATPase (out/in) Þ PAH into cell

luminal membrane: passive PAH diffusion (may be facilitated); PAH/urate (anion) exchanger

secretion of organic cations (TEA system) – weak organic base

basolateral membrane: facilitated diffusion driven by electronegative membrane potential
sequestering allows a greater intracellular concentration than through diffusion alone
luminal membrane: TEA/H⁺ (out/in) antiporter; Na/H (in/out) antiporter (powered by NaKATPase)

transporters may be occupied by endogenous substances

kidney metabolism of drugs could lead to a low estimate of tubular secretion; don’t pick it up in the urine, because it has been metabolized before excretion

basic drugs are often excreted as acidic metabolites (i.e. conjugates) Þ metabolized by kidney (conjugated)

tubular reabsorption: mostly though passive non-ionic diffusion

depends on: oil/water partition; concentration gradient; pK_a of the substance; pH; urine flow rate
water soluble drugs are not reabsorbed well

urate reabsorption: 90% of filtered urate (end product of purine metabolism, anion) is reabsorbed in humans Þ excess leads to gout

mechanism is still in debate; have small secretory route, larger reabsorptive route

basolateral membrane: urate/Cl exchanger mediates high affinity, low capacity secretion

inhibited by pyranzinoate and salicylate Þ prevent urate uptake Þ raise plasma urate

luminal (brush border) membrane: urate/PAH exchanger mediates low affinity,high capacity urate reabsorption in conjunction with anion secretion

exchanges urate for many anions (Cl, HCO₃, OH, lactate, anionic drugs)

low doses of anionic drugs can facilitate this exchanger and lead to more urate reabsorption

high doses can block the transporter and lead to lower urate reabsorption (i.e. probenecid in therapeutic doses blocks the exchanger Þ treatment for gout)

Therapeutic implications

highly ionized drugs tend to be rapidly cleared unless bound to plasma proteins or in tissues

drugs that are lipid soluble at the pH of urine are readily reabsorbed in the kidney tubules

osmotic diuretics can increase excretion of lipid soluble drugs by increasing urine flow and decreasing reabsorption

changing the urinary pH with bicarb. or arginine hydrochloride can alter excretion of WOB and WOA

i.e. low urine pH facilitates elimination of WOB by making them more water soluble and less reabsorbed

tubular secretion of one drug may inhibit secretion of another

tubular reabsorption of urate can be inhibited by large doses of uricorsuric agents (i.e. probenecid), but small doses actually accelerate the PAH/urate exchanger and may lead to retention of urate

problems:

(1) penicillin: WOA; secreted very well by renal tubules; need to stop secretion in order to get a therapeutic effect

give probenecid to compete with the PAH carriers and shut down penicillin secretion

(2) patient with gout self medicates with asprin (salicylate) Þ gout gets worse

low doses stimulate PAH/urate exchanger; need high doses to shut it down

(3) patient treated for gout with probenecid, thiazide treatment for hypertension leads to a return of gout

thiazide must be at low concentrations for hypertension, otherwise it is a diuretic

but at low concentrations, thiazide stimulates the PAH/urate exchanger Þ urate reabsorption

(4) the original cephalosporins caused renal toxicity in animals that could be prevented by probenecid

found that PAH exchanger brought cephalosporins into the cells but they couldn’t get out
led to development of cephalosporins that could escape from tubule cells and not cause toxicity