Distribution Handout.pptx

Distribution     Body Fluids Blood Data Capillaries in Organs Distribution Volume Body Composition from Pharmacokinetic Viewpoint Fat-free tissues: density d ~ 1.1 g/mL, varying  high water content (~70 %), decreases with age mainly due to reduction in extracellular water  lipophilic drug...

Distribution     Body Fluids Blood Data Capillaries in Organs Distribution Volume Body Composition from Pharmacokinetic Viewpoint Fat-free tissues: density d ~ 1.1 g/mL, varying  high water content (~70 %), decreases with age mainly due to reduction in extracellular water  lipophilic drug molecules bind to proteins and accumulate in membranes Body fat (adipocytes): d = 0.9 g/mL wome men  content (% body weight): n  mainly triglycerides essential 10-13 2-5  lipophilic drug molecules average 25-31 18--- accumulate in membranes and in triglyceride oil 24 that almost completely fills the adipocytes --- bind to proteins Total body water (% of body weight) Total Body Water 80 70 60 men 50 women 0 3 6 months 9 12 5 10 15 20 3 years 4 5 6 decades Body Fluids: Volumes intracellular water 57% other 4 % bon es e 5% tis su e 7% % ma 7 plas interstitial water + lymph 20% de ns Blood: Volumetric Data Volume of the blood – circulates about once per min  for adults ~70 mL/kg (about 5 L in the standard person)  for children ~80 mL/kg Vascular surface ~300 m2 Length of vasculature ~19,000 km Hematocrit - the volume fraction of formed elements ~0.45 Volume of plasma (5x0.55) ~2.8 L (3 L) 50% of the blood is contained in large veins Blood: Composition Plasma - rich in protein  albumin (~5x10-4 mol/L, 35-50 g/L)  a -glycoprotein (~1x10-5 mol/L) 1  lipoproteins (variable) erythrocytes, ~ 5 millions/ L leukocytes, ~ 5 thousands/ L platelets, ~ 500 thousands/ L chylomicra (fat droplets – present also in cytoplasm) Capillaries: Morphology Capillaries consist of: endothelial layer  a single layer of large, polygonal, flat cells  the cells are joined by interstitial cement substance, forming tight junctions  in the smallest capillaries, the cells may wrap around to join with themselves the basement membrane - a layer of matrix proteins glycocalyx – a glycoprotein layer, most complete in fenestrated capillaries, where it forms a diaphragm Capillaries: Cross-Sections The cross-sections are of irregular shape, nuclei of endothelial cells are bulging in. Average diameter: ~8 mm  erythrocytes pass through in a single file Minimum diameter ~4 mm  erythrocytes can only pass through the smallest capillaries in a slightly deformed form (as bent discs) Maximum diameter ~40 mm  in liver sinusoids Capillaries: Wall Porosity The capillary walls can be:  continuous  continuous endothelium, uninterrupted basement membrane  in brain and central nervous system - blood brain barrier, muscles, fat, skin, lungs, connective tissues, nephron (excluding glomerulus), placenta, testis  fenestrated  endothelial cells have trans-cellular fenestrae 30 - 80 nm in diameter, spanned with fibrous diaphragm (a part of glycocalyx), the basement membrane complete  in renal glomerulus, intestine, mammary glands, pancreas  discontinuous (typical, but not exclusive, for sinusoids)  endothelial layer has openings 100-300 nm in diameter, the basement membrane is missing  in bone marrow, spleen, liver (but also the first two types)  in tumors, the openings may have diameters up to 1.2  m Capillaries: Wall Permeability  Continuous capillary walls  barrier function  selective permeability based on drug properties  active protein-mediated transport for --- intake of nutrients (glucose, amino acids, ions) --- efflux of some substances (by P-glycoprotein, MDR proteins…)  Fenestrated capillary walls  permeable, even to small peptides  no selectivity besides size limitations  Discontinuous capillary walls  very permeable, even to albumin, other proteins, and cells (leukocytes, metastazing cancer cells)  no selectivity besides size limitations Capillaries: Density  Density depends on the function of the organ – remember the average capillary diameter ~8  m for the comparisons  High density in lungs  the interspaces are smaller than the capillaries themselves  Intermediate density  in kidney: the interspaces are about 3 the volume of capillaries  in brain, liver, myocardium: the interspaces are about 10the volume of capillaries  Low density  in muscles, fat, connective tissue: the interspaces are about 30the volume of capillaries  Most living cells lie within 20 cell layers from a capillary  Nearly all cells are within 100-200  m from a capillary Implications for Absorption/Distribution  The number of cell layers served by a capillary varies depending on the organ (approximate values): ~ 1 in lungs ~ 2 in kidneys ~ 5 in intestines, liver, heart, brain, and spleen ~ 15 in skin, muscles, fat, and bones  Each cell contains internal membranes – endoplasmic reticulum and the membranes of subcellular organelles  A good estimate of the number of membranes the drug molecules need to cross is the number of cell layers ×10  The slopes of the concentration-lipophilicity profiles in the final acceptor compartment are very steep, so that the profiles are narrow peaks specifying the optimum logPO value that ensures good penetration of the tissue Blood Flow through Organs organ lungs kidney liver brain skin fat muscles bones % of cardiac output blood flow (mL/min/g) 100 22 27 14 6 4 15 5 10 4 0.8 0.5 0.04 0.03 0.02 0.02 Volume of Distribution: Definition Vd is defined as the ratio of  the drug amount (n) and  the drug concentration in plasma (c ) P at any given moment t (1) The plasma concentration is lower and Vd is higher if there is a lot of distribution into tissues Vd is the measure of distribution into tissues Vd: Mental Visualization Vd is the volume of the body corrected for   membrane accumulation, characterized by the membrane/water partition coefficient P protein binding in plasma and tissues including extra- and intracellular proteins Vd is equal to the volume of the body (biosystem), if the drug is not  accumulated in the membranes (P = 1)  bound to the proteins Vd: Lower Limit Vd is the sum of the volume of plasma (VP) and corrected volumes of organs (VOCi) (2) The minimum value of Vd is the volume of plasma (VP). This happens when all drug is kept in plasma, and no drug distributes into tissues (all VOCi=0). This is observed for large-molecule biopharmaceutical or nanotechnology-derived drugs that cannot escape plasma and do not enter extracellular fluid. They cannot cross capillary walls (not even the fenestrated Vd Equal to Body Volume? The corrected volume of the organ no. i (VOCi) is the actual volume (VOi) corrected for membrane accumulation and protein binding using fraction unbound (fU) in plasma (P) and the organ (Oi): (3) The Vd is equal to the body volume only in an improbable situation when the fractions unbound are equal for plasma and for the tissues. Vd and Trapping Effect Equation 4 from Eqs 2 and 3 (4) tells that the volume of distribution is… …increased by stronger binding to tissue proteins and membranes (no upper limit) because this binding lowers fUOi …decreased by stronger binding to plasma proteins because this binding lowers fUP (if fUP  0, Vd  VP because VOCi  0). Range of Volume of Distribution Values (logarithmic scale) Vd and Drug Distribution I Vd is the sum of the volume of plasma (VP) and corrected volumes of organs (VOCi) (2) Multiplied by the plasma concentration (5) The drug amounts (n) in plasma and individual organs are in the same ratio as are the volumesV and V . Vd and Drug Distribution II For the standard patient, VP = 3 L. (2) So the drug amounts in plasma and tissues are in the same ratio as VP to (Vd - VP). Examples for the dose 100 mg: Vd (L) Ratio 10 100 1000 Amount in Plasma (mg) Amount in Tissues (mg) 3:7 30 70 3 : 97 3 97 3 : 997 0.3 99.7 Drug Distribution and Protein Binding Protein binding is mostly fast and non-covalent Protein binding serves as depot for drug molecules Protein binding ‘attracts’ the molecules to the given compartment - the total concentration for that compartment increases (see Eq 4)  if binding occurs in tissues, it increases V D  if binding occurs in plasma, it decreases V D Protein-bound drug molecules are prevented from metabolism and excretion, but also cannot elicit the effects Volume of Distribution: Affecting Factors