Module 2 # 2 Pharmacokinetics

absorption of drugs drugs can be given iv, im, sc, orally (po) if given parenterally, they should be water soluble oral absorption is more complex: tablet----dissolves in gut water----lipid soluble form crosses gut barrier-----must escape liver (first pass metabolism) amount absorbed is bioavailability

Which definition is correct? “Drug absorption refers to the passage of a drug from its site of administration into the circulation” –Brenner “Absorption describes the rate and extent to which a drug leaves its site of administration and reaches its site of action” –Goodman & Gilman

Pharmacokinetics (how the body handles drugs) (a,d,m,e) most drugs are weak acids or bases: HA H + + A - BH + B + H + only the non-ionized form can cross cell membranes when H increases get more HA and BH + even if the drug is not ionized, it still needs to be lipid soluble to cross cell membranes pH=pKa + log(base) (acid)

distribution of drugs once in the body, drugs distribute to tissues the ratio: amount in the body/plasma concentration is Volume of distribution (Vd) TBW= 0.6 L/Kg (42 l) ECF vol = 0.2 L/Kg (12 l) Plasma vol.= 0.05 L/Kg (3 l) Blood vol = 5.5 l some drugs assume these: Ethanol 0.54 l/kg Gentamicin 0.31 l/kg warfarin 0.14 l/kg

volume of distribution Cp 0 Vd = Dose (mg)/Cp 0 (mg/L)= Litres

volume of distribution-2 sometimes the Vd is anatomically “correct” (e.g. ethanol, gentamicin, warfarin) sometimes it’s not: (e.g.. THC 9L/Kg, amiodarone 66 L/Kg –highly lipd soluble lipid:plasma ratio >300:1) drugs with high Vd are often bound to tissue components (proteins or fat) drugs with low Vd are often bound to plasma proteins

Clarifying V d Vd is the ratio of the amount of drug in the body at any time (t) to the plasma concentration (C p ) at that time. The only time we can be absolutely sure of the amount of drug in the body is at time 0. This is the dose of the drug that we gave iv. We can’t measure directly the Cp0, but we can extrapolate it from later points in the log C p vs. time curve. When we calculate V d, we sometimes get an unrealistic number. We normalize V d to Litres/Kg of body weight. If the V d ethanol is 48 litres and the body weigh 80 Kg: the V d ethanol is 0.6 L/Kg

excretion filtration reabsorption secretion filtrationfree drug only, not protein bound reabsorptionpassive, lipid soluble form only (pH) secretionactive, acids and bases, saturable Plasma pH is constant; urine pH varies from

excretion-2 the renal clearance of a drug can be calculated: Cl drug =UV =Urinary conc. UVol = ml/min P Plasma conc GFR is 125 ml/min if the Cl drug is 125ml/min, it is filtered only if the Cl drug is <125ml/min, it is reabsorbed if the Cl drug is >125ml/min, it is secreted * free drug only if the drug is water soluble, the kidney can excrete it.

metabolism The purpose of drug metabolism is to render drugs water soluble, so they can be excreted by the kidney The liver is the main organ of metabolism 2 types: ¶ phase 1: oxidation, reduction, hydrolysis ¶ phase 2: conjugation (glucuronide, sulphate) oxidation via the cytochrome P450 system is important

metabolism -2 reduced CYP450 picks up O 2 and attaches it to the drug

metabolism -3 CYP3Alots of inhibitors and inducers CYP2D6genetic variants (codeine)- 10% of caucasians (Chinese produce less morphine from codeine and are also less sensitive to morphine) CYP2C9genetic variants (warfarin – 10-20% caucasians have a variant isoform – can’t inactivate warfarin efficiently – more sensitive ) many drugs use more than one CYP; saturable pathways

summary pharmacokinetics describes how the body handles drugs drugs get into and out of the body to move from one compartment to another, the drug must be lipid soluble which means non-ionized the kidney excretes water soluble drugs the liver metabolizes lipid soluble drugs CYP family is important