Clearance Determinations Arthur G. Roberts. Routes of Elimination.

Slides:



Advertisements
Similar presentations
Fig 1. Processes involved in urine formation
Advertisements

The Urinary System Adapted from
Urinary System.
Kidney Function Tests Contents: Kidney functions Functional units Renal diseases Routine kidney function tests Serum creatinine Creatinine clearance.
How does the kidney work? What controls the rate and concentration of urine? Review nephron in kidney Steps in urine formation and concentration Glomerular.
I. Urinary System A.Humans excrete nitrogenous waste (from amino acids) as urea and uric acid. B.Kidneys remove waste and water from blood.
1-C: Renal and Hepatic Elimination
The nephron and kidney function
Module 2 # 2 Pharmacokinetics absorption of drugs drugs can be given iv, im, sc, orally (po) if given parenterally, they should.
C8 FORMATION OF URINE BY THE KIDNEY. Today I am going to introduce: 1.the microstructure of the Kidney 2. glomerular filtration.
3 functions of the urinary system Excrete nitrogenous wastes – Urea produced from the metabolism of proteins and nucleic acids Other animals produce ammonia.
The Excretory System: Urine Formation
Kidney Function Tests Rana Hasanato, MD, KSFCB
Kidney Function Tests Contents: Functional units Kidney functions Renal diseases Routine kidney function tests Serum creatinine Creatinine clearance.
KIDNEY FUNCTIONS URINE FORMATION
Functions of the Kidneys  Regulation of extracellular fluid volume and blood pressure  Regulation of osmolarity--close to 300 mOsm  Maintenance of ion.
The Kidney.
Renal Clearance The renal clearance of a substance is the volume of plasma that is completely cleared of the substance by the kidneys per unit time.
Week 3 - Biopharmaceutics and Pharmacokinetics
3 functions of the urinary system Excrete nitrogenous wastes – Urea produced from the metabolism of proteins and nucleic acids Other animals produce ammonia.
Urinary System and the Excretion System
Urinary System. A. Functions - regulates volume, composition, and pH of body fluids; excretes N and S wastes; controls red blood cell production; regulates.
Dose Adjustment in Renal and Hepatic Disease
 This lesson explains how the kidneys handle solutes.  It is remarkable to think that these fist-sized organs process 180 liters of blood per.
PLASMA CLEARANCE AND RENAL BLOOD FLOW
Drug Disposition Porofessor Hanan hager Dr.Abdul latif Mahesar College of medicine King Saud University.
Excretion of Drugs By the end of this lecture, students should be able to Identify main and minor routes of Excretion including renal elimination and biliary.
LONGITUDNAL SECTION OF KIDNEY KLECOP, Nipani.
CLEARANCE CONCEPTS Text: Applied Biopharm. & PK
Quantitative Pharmacokinetics
Kidney Function Tests. Kidney Function Tests Contents: Kidney functions Functional units Renal diseases Routine kidney function tests Serum creatinine.
Nonlinear Pharmacokinetics
Excretory. Function Remove metabolic waste from the blood- Excretion Regulate H2O in blood Organs of excretion- Skin-water, salts and urea Lungs-CO2 Kidneys.
Kidney Function Tests.
Renal Excretion of Drugs
From A Physiologic Perspective Chemical Clearance from the Body
The Urinary System.
Do Now What do your kidneys do? What is excreted in urine?
Pharmacology Department
THE URINARY SYSTEM Chapter 20 – Page 774. Function  Maintain homeostasis through composition, pH, and volume  Excretes foreign substances.
PHARMACOKINETICS Part 3.
Glomerular filtration. Dr. Rida Shabbir DPT KMU. Functions of kidney: Excretion of metabolic waste products and foreign chemicals. Regulation of water.
Human Anatomy and Physiology Renal function. Functions Regulation of water and electrolytes Maintain plasma volume Acid-base balance Eliminate metabolic.
K + Homeostasis. The need: ECF K + concentration is critical for the function of excitable cells However, about 98% of is in K + ICF ICF concentration.
16.2 Anatomy of the Kidney and Excretion There are three regions to a kidney ___________ Nephrons are the functional units of the kidney  Each kidney.
Errata Lecture 10 Slide 18 Rational because However.
Excretion of Drugs By the end of this lecture, students should be able to Identify main and minor routes of Excretion including renal elimination and biliary.
Renal Physiology and Function Part II Renal Function Tests
Concepts of drug disposition Pharmacology Department
BIO 391- The Excretory System The Structure and Function of the Kidney.
Tubular reabsorption.
1 Renal Structure and Function. 2 Kidneys Paired Retroperitoneal Partially protected by the 11 th and 12 th ribs Right slightly lower due to liver Surrounded.
Dr. Rida Shabbir DPT IPMR KMU 1. Objectives Describe the concept of renal plasma clearance Use the formula for measuring renal clearance Use clearance.
Clearance and Renal Excretion Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics Faculty of Pharmacy Omer Al-Mukhtar University Tobruk,
Time Plasma Conc (hr) (mg/L) Below limit of detection 1 Compartment IV Analysis & Renal Elimination 500 mg of tobramycin.
Pharmacokinetics 2 General Pharmacology M212
DOSAGE ADJUSTMENT IN RENAL AND HEPATIC DISEASES Course Title : Biopharmaceutics and Pharmacokinetics – II Course Teacher : Zara Sheikh.
Intrinsic Clearance Arthur G. Roberts. Hydrophobic vs. Hydrophilic more bound to plasma proteins more distributed throughout body more metabolized.
Allie punke Pharmacokinetics tutoring Fall 2016
Pharmacokinetics.
Excretion of drugs.
Allie punke Pharmacokinetics tutoring Fall 2016
Chapter 6 EXCRETION OF DRUGS
Allie punke Pharmacokinetics tutoring Fall 2016
EXCRETORY SYSTEM.
Hawler Medical University
Biopharmaceutics Chapter-6
Renal Physiology Prof. K. Sivapalan..
Q1: Drug A is a small and hydrophilic compound that distributes to extracellular fluids only. It has a volume of distribution of 5.6 L in a healthy 70-kg.
Drug Metabolism.
Presentation transcript:

Clearance Determinations Arthur G. Roberts

Routes of Elimination

Zero versus First-Order Elimination

Zero Order

First Order

1 st Order Elimination rate of renal excretion = K renal * [Drug] rate of metabolism = K metabolism * [Drug] rate of biliary excretion = K biliary * [Drug] rate of other = K other * [Drug] Overall elimination = sum of all the rates Overall elimination = (K renal +K metabolism +K biliary +K other )*[Drug]

Clearance, Elimination and Excretion Clearance (Renal) (V/time, L/hr) Elimination (mass) (a.k.a. Extraction) Mechanisms for either – biotransformation (e.g. Cl int ) – excretion

Clearance efficiency for kidney or liver removal L/hour rapid or slow? – rel. large clearance and small volume distribution – rel. small clearance and large volume distribution rate of elimination (extraction) = Clearance * [Drug] plasma

Clearance Terms [Drug] in (mg/L) [Drug] out (mg/L) Q (L/h) Rate of Drug in = [Drug] in * Q Rate of Drug out = [Drug] out * Q Extraction Rate = ([Drug] in -[Drug] out ) * Q Extraction Ratio ([Drug] in -[Drug] out )/[Drug] in ) Clearance = E * Q Artery Vein

Example Rate Drug in, Rate Drug out, Extraction rate, extraction ratio, Clearance, Elimination Rate 1 L/(kg*hr) Kidneys Continuous IV infusion

Clearances

Clearance is additive sometimes Cl h

Elimination Rate Constant and Half Life Versus Clearance elimination rate = - K * Drug dose plasma = -Cl * [Drug] plasma K = Clearance (Cl)/Volume Distribution (Vd) T 1/2 = (ln 2)/K = (ln 2 * Vd)/Cl

Total Body Clearance [Drug] plasma

Renal Clearance Loop of Henle Proxima l Tubule Distal Tubule Collecting Duct

Glomerular Filtration Glomerulus Q at 1.2 L/min. or 72 L/hour prefer neutral 4-8 nm anionic albumin (7 nm) not filtered insulin (5 kD) filtered Normal glomerulus filtration rate 10% Q 7.2 L/ hour

Renal Clearance Neutral and small drug (< 8 nm) – not bound to plasma proteins Glomerular Filtration Rate (GFR) = Clearance (Cl GF ) – bound to plasma proteins fraction unbound (fu) * GFR = Cl GF Example: GFR = 9 L/hour fu = 30% CL GF = ?

Tubular Secretion

Tubular Reabsorption Lipophilicity pKa (acid and base forms)

Renal Clearance Renal Clearance (Cl r ) = Cl GF + Clearance from Tubular Secretion (Cl TS ) – Tubular Reabsorption (TR) Cl r = fu * GFR + Cl ts - TR

Renal Clearance Example Cl r = 1.8 L/hr GFR = 7.2 L/hr fraction bound = 80% What are the relative values for active tubular secretion (Cl TS ) and tubular reabsorption (TR)?

Renal Clearance [drug] plasma

Cl r Example PeriodVolume[Drug] urine Period[Drug] plasma Average Excretion Rate (mg/hour) = (Volume * [Drug] urine )/time 3 mg/hour = ( 0.2 *15)/1 mg/L hours L

Cl r Example PeriodAvg. Excretion Rate Period[Drug] plasma mg/L hours mg/hour slope = ( )/( ) slope = 2.72/0.219=12.4 L/hour=Cl r

Single-Point Determination of Renal Clearance Under Steady-State Conditions MeasurementAmountNormal Collection Period24 hours Volume Urine Collected 1.05 L Urinary Creatine Concentration 1140 mg/L mg/L Plasma Creatine Concentration 10 mg/L6-12 mg/L 55 year old 65 kg female What is the average Cl r ?

Hepatic Clearance Mechanisms Biotransformation Excretion

Restrictive and Non-restrictive Clearance Non-restrictive E h > 0.7 Restrictive E h < 0.3

Non-Restrictive Hepatic Clearance: High E h

Restrictive Hepatic Clearance: Low E h

Blood and Plasma Hepatic Clearance plasma = protein and water

Example Cl plasma hepatic = 54 L /hr Q hb = 78 L/hr fu=1 ([drug] plasma /[drug] blood ) = 0.3 What is the extraction ratio? Does the drug undergo restrictive or non- restrictive clearance?

End of Clearance Determinations