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1-C: Renal and Hepatic Elimination

1-C: Renal and Hepatic Elimination. 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the

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1-C: Renal and Hepatic Elimination

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  1. 1-C: Renal and Hepatic Elimination 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) The intent of this slide pack is to evaluate Renal Clearance of a drug … How much moxi is in the urine ? But first, although we have already analyzed plasma data, as a review calculate volume, AUC, K, half-life and clearance.Then: 1. How much unchanged moxi is in the urine at 12 hrs? ..at 36 hrs? Calculate K and ke. from urine data. 2. What is the ClR of moxifloxacin?

  2. 1-C: Renal and Hepatic Elimination 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) The intent of this slide pack is to evaluate Renal Clearance of a drug … How much moxi is in the urine ? But first, although we have already analyzed plasma data, as a review calculate volume, AUC, K, half-life and clearance.Then: 1. How much unchanged moxi is in the urine at 12 hrs? ..at 36 hrs? Calculate K and ke. from urine data. 2. What is the ClR of moxifloxacin?

  3. 1-Compartment IV Dosing Analysis of Concentration –Time Data This data set provided is identical in many ways to the tobramycin data set analysed in Slide Pak 07. While the solution to volume, AUC, K, half-life and clearance is shown briefly in the following slides, you should complete the calculation of these parameter values independently … for practice. Class time will not be spent reviewing the method of calculation of the initial concentration, AUC, K, half-life or clearance.

  4. 1-Compartment IV Dosing Analysis of Concentration –Time Data You need to calculate the initial concentration, AUC, K, half-life and clearance. You must FIRST determine the log of the concentration and then from any pair of points (or using all data in Excel) determine the slope. K is be determined from inspection of the data, graphical methods or by calculation of the slope.

  5. 1-Compartment IV Dosing Analysis of Concentration –Time Data Estimation of K. K is the slope of the line (t=2 to 12 hr) K = -2.303[log(C2) – log(C1)] / (t2 - t1) = -2.303[log(1.16) – log(2.32)] / (12 – 2) = -2.303[0.064 – 0.365] / (10) = -2.303[ - 0.301]/10 = 0.0693hr-1 T½ = 10.0 hr. Excel = 0.694 hr-1

  6. 1-Compartment IV Dosing K 0.0694 hr-1 Volume 150.12 L Analysis of Concentration –Time Data Using K, we can then estimate the initial concentration by extrapolation. Then calculate the volume & AUC by trapezoidal rule between each time point (or the pharmacokinetic method). A variety of estimates of K are possible given the concentrations. The Excel sheet (posted) provides a range of answers. Those calculated by hand should be very similar.

  7. 1-Compart.IV Dosing Volume 150.12 L AUC 38.38 mg*hr/L K 0.0694 hr-1 T½ 9.98 hr Cl 10.42L/hr

  8. 1-C: Renal and Hepatic Elimination 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) Parameter Estimates K = 0.0694 hr-1 T½ = 9.98 hr AUCI =38.38 mg*hr/L V = 150.12 L

  9. Graph Patient Data What model best describes this profile? Terminal elimination phase is log-linear… 1 Compartment Model with first order elimination (K)

  10. Graph Patient Data What model best describes this profile? It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)

  11. Graph Patient Data What model best describes this profile? It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) kH = kM1 + kM2 KNR = 20% excreted into bile as unchanged drug.

  12. Graph Patient Data What model best describes this profile? It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) K = ke + kH + kNR

  13. 1-C: Renal and Hepatic Elimination 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. The intent of this slide pack is to evaluate Renal Clearance of a drug … How much moxi is in the urine ? But first, although we have already analyzed plasma data, as a review calculate volume, AUC, K, half-life and clearance.Then: 1. How much unchanged moxi is in the urine at 12 hrs? ..at 36 hrs? Calculate K and ke. from urine data. 2. What is the ClR of moxifloxacin?

  14. 1-C: Renal and Hepatic Elimination 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. Urine collection following the 400-mg IV dose yields: Plasma Urine Amount Urinary Time Conc Collection Urine Urine Recovered Excretion (hr) (mg/L) Period Volume conc in Urine Rate (hr) (mL) (mg/L) (mg) (mg/hr) 0 no sample 22.32 0 – 4 290 0.060 17.40 61.76 4 - 8 295 0.045 13.28 121.16 8 - 16 490 0.036 17.64 240.50 16 - 32 1060 0.015 15.90 360.22 32 - 40 555 0.006 3.330

  15. 1-C: Renal and Hepatic Elimination 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. Calculate the Urinary excretion Rate (mg/hr): Amount recovered in urine / duration of urine collection. Plasma Urine Amount Urinary Time Conc Collection Urine Urine Recovered Excretion (hr) (mg/L) Period Volume conc in Urine Rate (hr) (mL) (mg/L) (mg) (mg/hr) 0 no sample 22.32 0 – 4 290 0.060 17.40 17.40 mg / 4 hr 61.76 4 - 8 295 0.045 13.28 121.16 8 - 16 490 0.036 17.64 240.50 16 - 32 1060 0.015 15.90 360.22 32 - 40 555 0.006 3.330

  16. 1-C: Renal and Hepatic Elimination 400 mg of moxifloxacin is administered by IV bolus to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. Calculate the Urinary excretion Rate (mg/hr): Amount recovered in urine / duration of urine collection. Plasma Urine Amount Urinary Time Conc Collection Urine Urine Recovered Excretion (hr) (mg/L) Period Volume conc in Urine Rate (hr) (mL) (mg/L) (mg) (mg/hr) 0 no sample 22.32 0 – 4 290 0.060 17.40 4.350 61.76 4 - 8 295 0.045 13.28 3.319 121.16 8 - 16 490 0.036 17.64 2.205 240.50 16 - 32 1060 0.015 15.90 0.994 360.22 32 - 40 555 0.006 3.330 0.416

  17. Renal Clearance of moxifloxacin When evaluating Aminoglycoside Renal Clearance (following IV dose with no metabolism and complete renal excretion) we observed: ClR = ClT and therefore, ClNR = 0 L/hr It would have also been apparent that the amount excreted in the urine after infinite time (Ae0-) would equal the dose. … that an Excretion Rate vs. Time plot had a slope proportional to K …that an Excretion rate vs. mid point plasma concentration had a slope equal to Renal clearance (ClR). But now, moxi has other routes of elimination…?

  18. Renal Clearance of moxifloxacin When evaluating Aminoglycoside Renal Clearance (following IV dose with no metabolism and complete renal excretion) we observed: ClR = ClT and therefore, ClNR = 0 L/hr It would have also been apparent that the amount excreted in the urine after infinite time (Ae0-) would equal the dose. … that an Excretion Rate vs. Time plot had a slope proportional to K …that an Excretion rate vs. mid point plasma concentration had a slope equal to Renal clearance (ClR). But now, moxi has other routes of elimination…? • Calculations to complete • 1. Plot Excretion rate vs. Time. • 2. Calculate K • 3. Plot Excretion rate vs. • mid-point plasma conc. • Calculate Renal clearance • Calculate ke • Determine Ae0- • Establish some principles • of Elimination

  19. 1-C: Renal and Hepatic Elimination Plot Excretion Rate vs. Time. Plot at the mid point of the collection period as this is the time which most accurately reflects the rate Plasma Urine Amount Urinary Time Conc Collection Urine Urine Recovered Excretion (hr) (mg/L) Period Volume conc in Urine Rate (hr) (mL) (mg/L) (mg) (mg/hr) 0 no sample 22.32 0 – 4 290 0.060 17.40 4.350 61.76 4 - 8 295 0.045 13.28 3.319 121.16 8 - 16 490 0.036 17.64 2.205 240.50 16 - 32 1060 0.015 15.90 0.994 360.22 32 - 40 555 0.006 3.330 0.416

  20. 1-C: Renal and Hepatic Elimination Plot Excretion Rate vs. Time Slope = -K/2.303

  21. 1-C: Renal and Hepatic Elimination Plot Excretion Rate vs. Time Urine Data Slope = -K/2.303 = - 0.030 K = -0.030 * -2.303 = 0.0687 hr-1 T½ = 10.084 hr

  22. 1-C: Renal and Hepatic Elimination Plot Excretion Rate vs. Time Change in the Rate at which drug appears in the urine ( Ex. Rate) is proportional to concentration in serum and slope is –K/2.303.

  23. Renal Clearance of moxifloxacin When evaluating Aminoglycoside Renal Clearance (following IV dose with no metabolism and complete renal excretion) we observed: ClR = ClT and therefore, ClNR = 0 L/hr It would have also been apparent that the amount excreted in the urine after infinite time (Ae0-) would equal the dose. … that an Excretion Rate vs. Time plot had a slope proportional to K …that an Excretion rate vs. mid point plasma concentration had a slope equal to Renal clearance (ClR). But now, moxi has other routes of elimination…? • Calculations to complete • 1. Plot Excretion rate vs. Time. • 2. Calculate K • 3. Plot Excretion rate vs. • mid-point plasma conc. • Calculate Renal clearance • Calculate ke • Determine Ae0- • Establish some principles • of Elimination

  24. 1-C: Renal and Hepatic Elimination Plot Excretion Rate vs. Mid-point Plasma concentration. Plot the excretion rate vs. the concentration at the mid point of the collection period Plasma Urine Amount Urinary Time Conc Collection Urine Urine Recovered Excretion (hr) (mg/L) Period Volume conc in Urine Rate (hr) (mL) (mg/L) (mg) (mg/hr) 0 no sample 22.32 0 – 4 290 0.060 17.40 4.350 61.76 4 - 8 295 0.045 13.28 3.319 121.16 8 - 16 490 0.036 17.64 2.205 240.50 16 - 32 1060 0.015 15.90 0.994 360.22 32 - 40 555 0.006 3.330 0.416

  25. 1-C: Renal and Hepatic Elimination Plot Excretion Rate vs. Mid-point Plasma concentration. Slope = ClR (L/hr)

  26. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion Slope = ClR (L/hr) = 1.864 L/hr

  27. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion. Slope = ClR (L/hr) CLR = 1.864 L/hr Plasma Data; ClT = 10.42 L/hr What does this tell us?

  28. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion. ClR = 1.864 L/hr ClT = 10.42 L/hr ClR / ClT = 0.1789

  29. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion If 17.89% of ClT is determined by ClR what is ClNR?

  30. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion If 17.89% of ClT is determined by ClR what is ClNR? ClT = ClR + ClNR ClNR = 10.4 – 1.8 ClNR = 8.55 L/hr

  31. Renal Clearance of moxifloxacin When evaluating Aminoglycoside Renal Clearance (following IV dose with no metabolism and complete renal excretion) we observed: ClR = ClT and therefore, ClNR = 0 L/hr It would have also been apparent that the amount excreted in the urine after infinite time (Ae0-) would equal the dose. … that an Excretion Rate vs. Time plot had a slope proportional to K …that an Excretion rate vs. mid point plasma concentration had a slope equal to Renal clearance (ClR). But now, moxi has other routes of elimination…? • Calculations to complete • Plot Excretion rate vs. Time. • Calculate K • Plot Excretion rate vs. • mid-point plasma conc. • Calculate Renal clearance • Calculate ke • Determine Ae0- • Establish some principles • of Elimination

  32. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion. • If 17.89% of ClT • is determined by ClR • ClT = ClR + ClNR • and • K = ke + knr • and K and ClT • are related by the • proportionality constant • Volume • what is ke?

  33. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion. If 17.89% of ClT is determined by ClR ClT = ClR + ClNR and K = ke + knr and K and ClT are related by the proportionality constant - Volume what is ke?

  34. 1-C: Renal and Hepatic Elimination Renal Clearance & Urinary Excretion. If 17.89% of ClT is determined by ClR ClT = ClR + ClNR and K = ke + knr and K and ClT are related by the proportionality constant - Volume what is ke? ClR ke ClT K ----- = ----- ClT = 10.42 L/hr and ClR = 1.864 L/hr K = 0.0687 hr-1 and ke = 0.01242 hr-1

  35. Renal Clearance of moxifloxacin When evaluating Aminoglycoside Renal Clearance (following IV dose with no metabolism and complete renal excretion) we observed: ClR = ClT and therefore, ClNR = 0 L/hr It would have also been apparent that the amount excreted in the urine after infinite time (Ae0-) would equal the dose. … that an Excretion Rate vs. Time plot had a slope proportional to K …that an Excretion rate vs. mid point plasma concentration had a slope equal to Renal clearance (ClR). But now, moxi has other routes of elimination…? • Calculations to complete • Plot Excretion rate vs. Time. • Calculate K • Plot Excretion rate vs. • mid-point plasma conc. • Calculate Renal clearance • Calculate ke • Determine Ae0- • Establish some principles • of Elimination

  36. Renal Clearance of moxifloxacin When evaluating Aminoglycoside Renal Clearance (following IV dose with no metabolism and complete renal excretion) we observed: ClR = ClT and therefore, ClNR = 0 L/hr It would have also been apparent that the amount excreted in the urine after infinite time (Ae0-) would equal the dose. However, now there is at least one other source of elimination (kNR which is likely made up of kH (or kM1 and kM2) and kB and since … If ke is determining how much drug appears in the urine then … ClR ke ClT K ----- = -----

  37. Renal Clearance of moxifloxacin However, now there is at least one other source of elimination (kNR which is likely made up of kH (or kM1 and kM2) and kB and since … If ke is determining how much drug appears in the urine then … Ae0- ke DoseIV K and and all will have a ratio of ~ 0.1789 in this patient. ClR ke ClT K ----- = ----- -------- = ----- ClR ke Ae0- ClT K DoseIV ----- = ----- = ---------

  38. Renal Clearance of moxifloxacin 67.55 mg Over the first 40 hours, 67.55 mg of moxi is collected in the urine. Based proportion of drug being eliminated into the urine (ke/K) the total amount expected in the urine would be 400 mg x 0.1789 = 71.56 mg. Would 4.01 mg be expected to appear in the urine after 40 hr? (40 hr  )

  39. Renal Clearance of moxifloxacin 67.55 mg Would 4.01 mg be expected to appear in the urine after 40 hr? (40 hr  ) At 40 hours, 0.16 mg/L of moxi remains in plasma. The estimated volume is 150.12 L. Therefore the amount remaining in the body at 40 hours is: 0.16 mg/L x 150.12 L =

  40. Renal Clearance of moxifloxacin 67.55 mg Would 4.01 mg be expected to appear in the urine after 40 hr? (40 hr  ) At 40 hours 0.16 mg/L of moxi remains in plasma. The estimated volume is 150.12 L. Therefore the amount remaining in the body at 36 hours is: 0.16 mg/L x 150.12 L = 24.6 mg The amount that should appear in the urine (40 hr  ) would be: 0.1789 x 24.6 =

  41. Renal Clearance of moxifloxacin 67.55 mg Would 4.01 mg be expected to appear in the urine after 40 hr? (40 hr  ) At 40 hours 0.16 mg/L of moxi remains in plasma. The estimated volume is 150.12 L. Therefore the amount remaining in the body at 40 hours is: 0.16 mg/L x 150.12 L = 24.6 mg The amount that should appear in the urine (40 hr  )would be: 0.1789 x 24.6 = 4.29 mg

  42. Renal Clearance of moxifloxacin When evaluating Aminoglycoside Renal Clearance (following IV dose with no metabolism and complete renal excretion) we observed: ClR = ClT and therefore, ClNR = 0 L/hr It would have also been apparent that the amount excreted in the urine after infinite time (Ae0-) would equal the dose. … that an Excretion Rate vs. Time plot had a slope proportional to K …that an Excretion rate vs. mid point plasma concentration had a slope equal to Renal clearance (ClR). But now, moxi has other routes of elimination…? • Calculations to complete • Plot Excretion rate vs. Time. • Calculate K • Plot Excretion rate vs. • mid-point plasma conc. • Calculate Renal clearance • Calculate ke • Determine Ae0- • Establish some principles • of Elimination

  43. Principals of Elimination Equations K = ke + kH + kNR TBC = ClT = ClR + ClH + ClNR ClH = ClM1 + ClM2 kH = kM1 + kM2 ClR = keV Change in the Rate at which drug appears in the urine ( Ex. Rate) is proportional to concentration in serum and slope is –K/2.303. Slope of log Excretion Rate vs. Time is proportional to K (-2.303) ClR ke ke Ae0- ClT K k10 DoseIV ----- = ----- = ----- = --------- the amount excreted in the urine after infinite time (Ae0-) equals ke/K …that an Excretion rate vs. mid point plasma concentration has a slope equal to Renal clearance (ClR).

  44. Summary of Urinary Elimination Change in the Excretion Rate at which drug appears in the urine [Slope (Log) Ex. Rate) vs.Time] is parallel the slope of the Concentration in serum vs. Time Slope is –K/2.303. This is true regardless of the proportion of the dose excreted into the urine ... as long as Ae0- >0 the amount excreted in the urine after infinite time (Ae0-) equals ke/K

  45. Summary of Urinary Elimination K is the overall rate constant which determines the half-life. ke determines the proportion of the dose excreted into the urine. Ae0- ke DoseIV K -------- = ----- the amount excreted in the urine after infinite time (Ae0-) equals ke/K …that an Excretion rate vs. mid point plasma concentration has a slope equal to Renal clearance (ClR).

  46. Summary of Urinary Elimination Second use of Excretion Rate: If Excretion Rate is plotted (not Log Excretion Rate) vs. mid point plasma concentration …slope is equal to Renal clearance (ClR). Minimum requirement is a single blood sample drawn at the mid point of the urine collection interval.

  47. Summary of Urinary Elimination • What do you need to calculate K? • At least 2 blood (plasma) concentrations drawn • at known times. • (ii) At least 2 urine collections of known intervals and time since the dose. • Plot Log Excretion Rate • vs. • Time

  48. Summary of Urinary Elimination • What do you need to • calculate ke? • A complete urine collection and a known dose • Ae0- ke • DoseIV K • (ii) Through relationships with other variables • ---- = ----- = ----- -------- = ----- ClR ke Ae0- ClT K DoseIV

  49. Summary of Urinary Elimination What do you need to calculate ClR? Minimum requirement is a single blood sample drawn at the mid point of the urine collection interval. If Urinary Excretion Rate is plotted vs. mid point plasma concentration …slope is equal to Renal clearance (ClR).

  50. Renal Function & Drug Clearance ClR Renal Excretion is based on: Filtration at the glomerulus. This is a function of a number of competing pressures. The hydrostatic pressure of blood is the overall driving force filtering blood. Working against this pressure is the osmotic pressure of the blood to hold on to the fluid and the hydrostatic pressure of the capsule. The result of these completing pressures is a net ~10 mmHg pushing fluid through the capsule and into the proximal tubule. In addition to filtration, there is active secretion, in the proximal renal tubule and reabsorption most likely in the distal tubules. Remaining Slides in this file are for interest only. Creatinine clearance will be covered in the 2nd term.

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