HLTH 340 Lecture A4 Toxicokinetic processes: Distribution (part-1) NOTICE: These materials are subject to Canadian copyright and are presented here as images published in journals and books for which the University of Waterloo holds a licensed electronic subscription. These materials are provided to HLTH 340 students for their exclusive use though a non-public courseware system (UW-LEARN) and the images are restricted to the use of HLTH 340 students. Reproduction, transmittal, copying, or posting of these images by students in any form, electronic or physical, is strictly prohibited.

Distribution kinetics distribution is second phase of toxicokinetic ADME processes describes processes that determine where in the body a xenobiotic will go after absorption disposition = distribution + metabolism clearance = metabolism + excretion factors affecting the distribution kinetics of a xenobiotic anatomical structure of blood circulation at site of absorption (first-pass effect) partitioning of xenobiotic transport between blood components patterns of blood flow after absorption (perfusion kinetics) blood-tissue partitioning (tissue bioavailability) internal membrane barriers tissue sequestration mechanisms (depots and sinks) depot mobilization mechanisms effect of metabolic biotransformation reactions ionic trapping and redox trapping of xenobiotics (or their metabolites) in a tissue

First-pass effect by the liver filtered blood to systemic circulation xenobiotics in food and water carried from gut to liver via hepatic portal vein xenobiotics circulating in systemic blood are carried to liver via hepatic artery liver filters out a fraction of lipophiles into hepatocytes remaining lipophiles enter the systemic circulation via hepatic vein hepatocytes secrete their intracellular lipophiles to bile biliary excretion carries lipophiles to gut --> feces lipophiles systemic blood to liver bile to GI tract blood from GI tract

Blood Partitioning: binding of xenobiotics to plasma proteins and erythrocytes bound toxicant (erythrocytes) xenobiotics are carried dissolved in blood plasma in 2 phases free plasma phase -- molecules dissolved as free solute in water protein bound phase – molecules reversibly (loosely) bound to large plasma proteins hydrophiles readily dissolve in water phase of blood plasma carried mainly in free plasma phase exception: most metal ions are carried by specific metal ion transporter proteins lipophiles tend to bind to plasma protein phase of blood plasma carried mainly in protein bound phase plasma proteins albumin (most common) -- prefers neutral lipophilic and mildly acidic xenobiotics (about 50 sites per protein) various types of lipoproteins -- prefers strongly lipophilic molecules special carrier proteins (e.g. transferrin for iron and some other metal ions) erythrocytes (RBCs) can selectively bind certain metal ions (e.g.iron, zinc, lead)

Free-plasma and erythrocyte-bound xenobiotics example: lead binding to ALAD protein plasma Pb++ erythrocyte Pb++ blood Pb++

Free-plasma and erythrocyte-bound xenobiotics example: lead binding to ALAD protein CNS (brain) spongy bone kidney CNS (brain) spongy bone kidney higher neurotoxicity lower neurotoxicity higher renal toxicity avg plasma Pb++ lower plasma Pb++ avg erythrocyte Pb++ higher erythrocyte Pb++ average blood Pb++ elevated blood Pb++ - - ALAD-1 polymorphism ALAD-2 polymorphism

Tissue distribution and bioavailability influences the ‘ ‘target tissue’ and the ‘critical effect’ xenobiotics often produce their primary toxic effects on specific tissues or organs toxic effect is possible only when a xenobiotic is able to be absorbed from the site of entry into the blood and then is distributed preferentially from the blood to the specific target tissue (where it is harmful) bioavailability extent of (1) absorption and (2) distribution of a xenobiotic to the target tissue (expressed as a fraction or % of the total dose) critical effect defined as the toxic effect observed in an essential physiological process at the lowest administered dose percentage of xenobiotic undergoing absorption from GI tract to blood (oral bioavailability) fraction of xenobiotic freely dissolved in blood plasma (effective blood concentration) degree of permeation of xenobiotic from blood into a specific tissue (tissue/blood partition) xenobiotic uptake at the target tissue is affected by several types of distribution factors tissue perfusion rate by arterial blood supply tissue/blood partition coefficient Kp (tissue/blood) internal membrane barriers (e.g. BBB) sequestration in non-target issues

Perfusion-limited and partition-limited tissue distribution perfusion-limited tissue distribution tissue perfusion rate defines rate of blood flow to organs highly perfused tissues (often more vulnerable) liver, kidneys, lung, brain poorly perfused tissues (often less vulnerable) skin, fat, connective tissues, bone, muscle (variable) partition-limited tissue distribution xenobiotics partition differentially between high-fat and low-fat content in tissues mainly determined by Kow partition coefficient (lipophilic vs hydrophilic) • high fat tissues -- adipose tissue (fat), brain, lungs, reproductive organs • low fat tissues -- heart, kidney, muscles, connective tissue also may be affected by carrier-mediated transport of ionic or polar xenobiotics using selective membrane channels or pumps e.g. lead: can be transported into tissues using the calcium or iron transporter channels also may be affected by liver metabolism of a xenobiotic to its metabolite(s) e.g. bisphenol A (BPA) is lipophilic --> binds to plasma proteins (albumin) --> persists in body bisphenol A glucuronide metabolite (BPA-gluc) is hydrophilic --> rapidly excreted by kidneys

PBPK computer model simulating the ADME toxicokinetics of an inhaled xenobiotic (e.g. chloroform) chloroform (IN) chloroform (OUT) Kp tissue/blood partition defines distribution Kp tissue/blood arterial blood IN venous blood OUT perfusion defines distribution Kp tissue/blood Q = tissue perfusion rate metabolism defines distribution C = blood concentration