1.3 Distribution & Excretion

passive transport

high → low; facilitates (protein transporters, channels)

active transport

low → high; primary active (ATP)

-symport and antiport

absorption variability

F: bioavailability

K_a: absorption rate constant

age effects on drug absorption

reduction in gastric acid & pepsin, reduced intestinal bloodflow

food can alter bioavailability

delay gastric emptying, stimulate bile flow, change GI pH, increase blood flow to large organs (splanchnic)

-affects absorption

food effect example (eythromycin)

do not take food

food and disease effect on controlled release budesonide

absorption enterocyte permeability

transcellular: carrier-mediated & passive lipoidal diffusion

paracellular: passive diffusion

first pass effect

goes through GI, absorbed in portal vein, nutrients go through liver (either metabolized or put into circulation)

-amount in circulation = bioavailability

drug distribution

dose → central compartment (blood, liver, kidney) ⇌ peripheral component (fatty tissue) → elimination

distribution tissues

fatty tissue, proteins, highly vs less perfused, CNS, placenta, muscle, specific organs

hydrostatic pressure

difference in pressure between arterial & venous capillary blood

-responsible for movement of water-soluble drugs into spaces between endothelial cells (and possibly lymph)

rate of diffusion

D = diffusion coefficient (cm²/s)

A = surface area of membrane (cm²)

K = partition coefficient (drug’s lipid solubility)

C₁-C₂ = concentration difference across membrane

h = membrane thickness (cm)

larger A

more absorption surface

higher K

more lipophilic drugs cross membrane more easily

diffusion of drug from capillaries to interstitial spaces

blood plasma, interstitial & lymph fluids, tissues, and other body water

highly perfused

heart, brain, kidney, endocrine glands, skin, muscle, fat, marrow

slowly perfused

bone, ligaments, tendons, cartilage, teeth, hair

major water volumes in a 70 kg human

blood (4.5-5 L) → plasma (3 L) + blood cells (2 L)

-extracellular water (15 L) → plasma (3 L) + interstitial water (12 L)

-intracellular water (27 L)

CNS

brain, cerebrospinal fluid, blood brain barrier (least permeable capillaries)

-brain + choroid plexus have tight junctions

placenta

fetus is exposed to all drugs taken by mother

placental drug transporters

BCRP (breast cancer resistance protein)

MDR (multidrug resistance protein)

MRP (multidrug resistance-associated protein)

NET (noradrenaline transporter)

OAT (organic anion transporter)

OATP (organic anion-transporting polypeptide)

OCTN (novel organic cation transporter)

SER (serotonin transporter)

protein binding

drug can circulate in plasma in a free state, or bound to plasma proteins; usually reversible

-albumin carries acidic drugs, α-1-acid glycoprotein carries basic drugs

apparent volume of distribution (V_D)

C_P = D/V_D

relationship between dose given & concentration from central compartment

distribution and elimination phases

C_P = Ae^-αt (distribution) + Be^-ßt (elimination)

multicompartment PK