From A Physiologic Perspective Chemical Clearance from the Body Objectives for Today Problems / Questions & Review concerning Chemical Distribution …? A Physiologic View of Chemical Clearance from the Body Develop a definition for Clearance.

With time, where does the drug go? Clearance With time, where does the drug go? Why are drugs lost from the body? How are drugs lost from the body? Based on random flow? Like the elimination of an coloured gas or odour from a room or …?

Blood Flows1 Tissue Weight % Blood % Cardiac or (kg) of Flow Output3 Organ IBW (mL/min) Kidneys 0.16 0.23 1200 23 Adrenals 0.011 0.02 65 1.2 Thyroid 0.03 0.04 165 3.2 Brain 1.35 1.93 729 14 Liver 1.5 2.14 3002 5.8 Muscle 28 40 850 16 Skin 18 26 260 5.0 Fat 10 15 105 2.0 Spector, WS. Handbook of Biological Data Includes only arterial flow; total equals about 1500 mL/min. (25%) Cardiac Output / 70 kg = 5-6 L/min [85 mL/min/kg]

With time, where does the drug go? Clearance With time, where does the drug go? Organs are strategically arranged (liver – to deal with entry & elimination of compounds and are well perfused tissues. If a drug is eliminated by an organ (kidney or liver), the organ will have access to a greater amount of drug if a larger percentage of drug is found in the blood / plasma or serum. Theophylline 9.8% Levo: 3.5% / 4.2% Cipro: 2.9 % Cyclosporin: 0.15%

Clearance With time, where does the drug go? Organs are strategically arranged (liver – to deal with entry & elimination of compounds and are well perfused tissues. The blood emerging from an eliminating organ has a lower concentration than the blood entering the organ. This effectively dilutes the drug concentration in the primary storage area … the rest of the body.

Drug is “cleared” by the organ. Focus on an Eliminating Organ Pump Clearing Chamber Blood leaving the organ has a lower drug concentration than drug entering. Drug is “cleared” by the organ. The efficiency of Removal is quantified by the Extraction Ratio [ER].

Focus on an Eliminating Organ Ca Cv Extraction Ratio can be viewed as the proportion of drug removed during passage through the organ.

Focus on an Eliminating Organ Ca Cv Extraction Ratio can be viewed as the proportion of drug removed during passage through the organ. At constant concentration (steady – state) extraction can be estimated from the difference between arterial and venous concentrations. ER = [ (Ca – Cv) / Ca ] where Ca is the concentration in the artery on entry to the organ and and Cv is the concentration in the vein on exit from the organ

Clearance = Q x ER (mL/min) Focus on an Eliminating Organ Pump Clearing Chamber Clearance of drug is dependant on 2 factors: Efficiency of Removal [ER] and The rate at which drug can be delivered to the organ [Flow Rate: Q]. Clearance = Q x ER (mL/min)

ClH = Q [ (Ca – Cv) / Ca ] = Q*ER Focus on an Eliminating Organ At constant concentration (steady – state) clearance can be estimated from blood flow and the difference between arterial and venous concentrations. ClH = Q [ (Ca – Cv) / Ca ] = Q*ER or Cl = Q x ER where ER is the Extraction Ratio and Q is organ blood flow. When we focus on a single organ, Hepatic Clearance would be symbolized by ClH and Renal Clearance by CLR

ClTOTAL = ClHEPATIC + ClRENAL + ClLUNG Focus on an Eliminating Organ When we focus on a single organ, Hepatic Clearance would be symbolized by ClH and Renal Clearance by CLR … ClTOTAL = ClHEPATIC + ClRENAL + ClLUNG Clearance as the units of Volume per time (mL/min) Definition: Clearance: The volume of distribution volume of the sampled fluid from which drug is irreversibly removed per unit time.

QRBLOOD = 25% CO Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 mL/kg/min 70 kg male Creatinine Clearance = ~ 120 mL/min (serum) QRBLOOD = 25% CO

QRBLOOD = 25% CO QRSERUM = QRBLOOD Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 mL/kg/min 70 kg male Creatinine Clearance = ~ 120 mL/min (serum) QRBLOOD = 25% CO = 0.25 (85) = 21.25 mL/min/kg QRSERUM = QRBLOOD Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

QRBLOOD = 25% CO QRSERUM = QRBLOOD (0.55)(70) Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 mL/kg/min 70 kg male Creatinine Clearance = ~ 120 mL/min (serum) QRBLOOD = 25% CO = 0.25 (85) = 21.25 mL/min/kg QRSERUM = QRBLOOD (0.55)(70) = 820 mL/min (serum) ER = Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

QRBLOOD = 25% CO QRSERUM = QRBLOOD (0.55)(70) Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 mL/kg/min 70 kg male Creatinine Clearance = ~ 120 mL/min (serum) QRBLOOD = 25% CO = 0.25 (85) = 21.25 mL/min/kg QRSERUM = QRBLOOD (0.55)(70) = 820 mL/min (serum) ER = 120/820 = 0.146 or 14.6% Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Ciprofloxacin? Cardiac Output (Renal)= 820 mL/min (serum) Cipro Clearance = 35 L/hour (serum) = Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

QRSERUM = QRBLOOD Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Ciprofloxacin? Cardiac Output (Renal)= 820 mL/min (serum) Cipro Clearance = 35 L/hour (serum) = 583 mL/min QRSERUM = QRBLOOD Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

QRSERUM = QRBLOOD (0.55)(70) Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Ciprofloxacin? Cardiac Output (Renal)= 820 mL/min (serum) Cipro Clearance = 35 L/hour (serum) = 583 mL/min QRSERUM = QRBLOOD (0.55)(70) = 820 mL/min (serum) ER = Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

QRSERUM = QRBLOOD (0.55)(70) Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Ciprofloxacin? Cardiac Output (Renal)= 820 mL/min (serum) Cipro Clearance = 35 L/hour (serum) = 583 mL/min QRSERUM = QRBLOOD (0.55)(70) = 820 mL/min (serum) ER = 583/820 = 0.71 or 71% Very efficient Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

Male Acute Community Acquired Pneumonia to Cipro Pharmacokinetics Physiologic Approach to Cipro Pharmacokinetics Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q Male with Pneumonia Given the clearance of ciprofloxacin, how much drug is required each day to maintain an average concentration of 2 mg/L? (peaks of 3-4; troughs ~0.5) Age: 45 yr Weight: 80 kg Drug: Ciprofloxacin Serum ciprofloxacin concentrations average 2 g/mL (mg/L) Cipro Volume: 1.5 L/kg Cipro Am’t in body: Cipro Clearance:

Male Acute Community Acquired Pneumonia to Cipro Pharmacokinetics Physiologic Approach to Cipro Pharmacokinetics Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q Male with Pneumonia Given the clearance of ciprofloxacin, how much drug is required each day to maintain an average concentration of 2 mg/L? (peaks of 3-4; troughs ~0.5) Age: 45 yr Weight: 80 kg Drug: Ciprofloxacin Serum ciprofloxacin concentrations average 2 g/mL (mg/L) Cipro Volume: 1.5 L/kg Cipro Am’t in body: = 80 x 1.5 x 2 = 240 mg Cipro Clearance: = 35 L/hr = 840 L/day

Male Acute Community Acquired Pneumonia to Cipro Pharmacokinetics Physiologic Approach to Cipro Pharmacokinetics Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q Male with Pneumonia Given the clearance of ciprofloxacin, how much drug is required each day to maintain an average concentration of 2 mg/L? (peaks of 3-4; troughs ~0.5) Age: 45 yr Weight: 80 kg Cipro Clearance: = 840 L/day Average concentration over a day 2 mg/L Dose required to maintain [ ] = 2 (840) mg = 1680 mg/day

Focus on an Eliminating Organ How Efficient is a Normal Liver in removing Theophylline? Cardiac Output = 6.0 L/min Proportion of CO to the Liver = 25% Liver Blood Flow = 1.5 L/min Proportion of Blood as Serum = 55% Liver Serum (plasma) Flow = 1.5 L/min = 0.82 L/min OR = 820 mL/min Cardiac Output = 85 mL/kg/min 70 kg male Liver Serum (plasma) Flow = 85 * 70 * 0.55 * 0.25 = 818.12 mL/min Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

Focus on an Eliminating Organ How Efficient is a Normal Liver in removing Theophylline? Cardiac Output = 6.0 L/min (Blood) Liver Plasma Flow = 820 mL/min/70 kg male Theophylline: 85% metabolized 15% excreted unchanged Total clearance ~ 0.7 mL/min/kg = 50 mL/min (serum) Hepatic Clearance ClH = Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

QHBLOOD = 820 mL/min (serum) Focus on an Eliminating Organ How Efficient is a Normal Liver in removing Theophylline? Cardiac Output = 6.0 L/min (Blood) Liver Plasma Flow = 820 mL/min/70 kg male Theophylline: 85% metabolized 15% excreted unchanged Total clearance ~ 0.7 mL/min/kg = 50 mL/min (serum) Hepatic Clearance ClH = 50(0.85) = 42.5 mL/min QHBLOOD = 820 mL/min (serum) ER = Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

QHBLOOD = 820 mL/min (serum) Focus on an Eliminating Organ How Efficient is a Normal Liver in removing Theophylline? Cardiac Output = 6.0 L/min (Blood) Liver Plasma Flow = 820 mL/min/70 kg male Theophylline: 85% metabolized 15% excreted unchanged Total clearance ~ 0.7 mL/min/kg = 50 mL/min (serum) Hepatic Clearance ClH = 50(0.85) = 42.5 mL/min QHBLOOD = 820 mL/min (serum) ER = 42.5/820 = 0.052 or 5.2% Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q