2004-2005

2004-2005

Module 2# 2

Pharmacokinetics

2004-2005

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

2004-2005

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

2004-2005

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)

2004-2005

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

2004-2005

volume of distributionCp0

Vd = Dose (mg)/Cp0 (mg/L)= Litres

2004-2005

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

2004-2005

Clarifying Vd

• Vd is the ratio of the amount of drug in the body at any time (t) to the plasma concentration (Cp) 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 Cp vs. time curve.

• When we calculate Vd, we sometimes get an unrealistic number.

• We normalize Vd to Litres/Kg of body weight. If the Vd ethanol is 48 litres and the body weigh 80 Kg: the Vd

ethanol is 0.6 L/Kg

2004-2005

excretionfiltration reabsorption

secretion

• filtration free drug only, not protein bound• reabsorption passive, lipid soluble form only (pH)• secretion active, acids and bases, saturable

Plasma pH is constant; urine pH varies from 5.0-8.0

2004-2005

excretion-2

the renal clearance of a drug can be calculated:

Cldrug = UV = Urinary conc. UVol = ml/min P Plasma conc

GFR is 125 ml/min

• if the Cldrug is 125ml/min, it is filtered only• if the Cldrug is <125ml/min, it is reabsorbed• if the Cldrug is >125ml/min, it is secreted

* free drug only

if the drug is water soluble, the kidney can excrete it.

2004-2005

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

2004-2005

metabolism -2

reduced CYP450 picks up O2 and attaches it to the drug

2004-2005

metabolism -3

• CYP3A lots of inhibitors and inducers• CYP2D6 genetic variants (codeine)- 10% of caucasians(Chinese produce less morphine from codeine and are also less sensitive to morphine) • CYP2C9 genetic 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

2004-2005

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

2004-2005