Drug excretion 1Contents ... • Renal excretion • Creatinine clearance
Excretion The removal of a drug molecule from the body without chemical modification. Generally in urine, but occasionally in bile etc.
Kidney Glomerular Fitration Rate (GFR) 125ml/min Urine 1ml/min Plasma flow 650ml/min Acid Base 99% of H20 + Lipid soluble drugs Active Filtration secretion Reabsorption
Processes involved in renal excretion: 1Filtration • Passive process (Pressure driven) • 20% of plasma volume is filtered • Small molecules - Yes • Large molecules - No • Most proteins not filtered. Drugs which are extensively protein bound will also not be filtered.
Processes involved in renal excretion: 2Active secretion • Energy requiring • Can generate positive concentration • gradients • Two separate mechanisms for acids & bases • Saturable • Possible interactions
Processes involved in renal excretion: 2Active secretion ACIDSBASES Furosemide Quinine Penicillins Quaternary Probenecid ammonium salts Probenecid and penicillins share same mechanism. Probenecid competes with penicillins. Penicillin clearance reduced.
Processes involved in renal excretion: 3Reabsorption • 99% of water is reabsorbed • Lipid soluble drugs reabsorbed along • with the water. • Only very water soluble molecules can • be efficiently excreted by the kidneys.
Ion trapping Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium bicarbonate may be given to make the urine alkaline Urine Rest of body pH 8.0 pH 7.4 Non-ionised Non-ionised Ionised Ionised Barbiturate moves into urine - eliminated from body.
High renal clearance If renal clearance is greater than G.F.R. then there must be active secretion. Max possible renal clearance is approx. 650 ml/min (All plasma cleared). e.g. Aminohippuric acid
Low renal clearance • If clearance is much less than G.F.R. then either: • Not filtered or • Extensively reabsorbed • e.g. antipyrine, thiopental
Creatinine clearance • Creatinine is a waste product formed continuously by muscle. • Filtered by kidneys Creatinine clearance • Almost no active secretion approximately equals • Almost no reabsorption filtration rate (G.F.R.) • Creatinine clearance used as an estimate of G.F.R.
Why are creatinine clearance and GFR important in ADME? The clearances of many renally excreted drugs are closely linked to GFR. e.g. The clearance of gentamicin approximately equals GFR and therefore also approximates to creatinine clearance. When calculating a dosage regime we can assume that gentamicin clearance will equal creatinine clearance
Factors influencing serum creatinine concentration • 1) Creatinine production rate depends upon muscle mass, which in turn depends upon: • Body weight • Age (% muscle declines with age) • Sex (Men have higher % muscle than women) • 2) Creatinine clearance rate
Cockcroft & Gault Cockcroft & Gault took a series of individuals and measured their serum creatinine concentrations, ages, weights and creatinine clearances and found the following relationships: SrCr = 1.23 x (140 – Age) x Wt ……….…. in men CrCl SrCr = 1.04 x (140 – Age) x Wt …………. in women CrCl These can then be re-arranged to produce equations that estimate creatinine clearance.
Estimating creatinine clearance Cockcroft & Gault equation Men: CrCl = 1.23 x (140 – Age) x Wt SrCr Women: CrCl = 1.04 x (140 – Age) x Wt SrCr CrCl = Creatinine clearance (ml/min) Age (Years) Wt = Weight (kg) SrCr = Serum creatinine (μmol/l) No. You do not need to learn these equations!
Cockcroft & Gault equation Applicability: There are some situations where the equation is not applicable (e.g. children and in pregnancy.) There may also be an over-estimate of creatinine clearance in obese subjects, because large amounts of fat are included in the body weight, but this does not produce creatinine. “Ideal” body weight (based on height and build) will produce a better estimate.
Case • A woman, 30 years of age, weighing 70Kg, with a serum creatinine of 71 μmol/l . • Will receive 100mg gentamicin 3 times daily (i.v.) • Target peak concs are 4-8 mg/L trough concs < 2mg/L • Predict Css,max and Css,min. • Will regime be satisfactory?
Outline approach • Estimate creatinine clearance (and assume • gentamicin clearance to be the same) • Predict V from population data • Predict K from clearance and V • Predict Css,max and Css,min • Compare against desirable concentrations.
Estimate creatinine clearance For women: CrCl = 1.04 x (140 – Age) x Wt SrCr CrCl = 1.04 x (140 – 30) x 70 71 = 113 ml/min = 6.8 L/h Now assume that gentamicin clearance will also be 6.8 L/h
Predict V and K V = 0.25 L/Kg x 70 Kg = 17.5 Litres Cl = K.V K = Cl / V = 6.8 L/h 17.5 L = 0.389 h-1
Predict Css,max & Css,min Css,max = D/V . 1/(1-e-Kt) = 100mg/17.5L . 1/(1-e-0.389h-1 x 8h) = 5.71mg/L . 1/(1 - e-3.112) = 5.71mg/L . 1/(1 - 0.0445) = 5.71mg/L . 1/0.956 = 5.97 mg/L Css,min = Css,max - D/V = 5.97 - 5.71 mg/L = 0.26 mg/L
Compare to desirable concentrations Desirable Predicted OK? --------------------------------------------------------- Css,max 4-8 mg/L 5.97 mg/L Css,min <2 mg/L 0.26 mg/L The regime should be satisfactory
Terms with which you should be familiar ... • Filtration • Active secretion • Reabsorption • Glomerular Filtration Rate (GFR) • Creatinine clearance
What you should be able to do • Describe the various processes by which drugs may be added to or removed from urine. • Describe how adjustment of urinary pH may be used to enhance drug excretion in cases of overdose. • Estimate creatinine clearance from serum creatinine concentration, body weight, age and gender.