Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Tissue Drug Concentration

Author(s): Pietro Fagiolino and Marta Vázquez*

Volume 28, Issue 14, 2022

Published on: 07 June, 2022

Page: [1109 - 1123] Pages: 15

DOI: 10.2174/1381612828666220422091159

Price: $65


Blood flow enables the delivery of oxygen and nutrients to the different tissues of the human body. Drugs follow the same route as oxygen and nutrients; thus, drug concentrations in tissues are highly dependent on the blood flow fraction delivered. Although the free drug concentration in blood correlates with pharmacodynamics, the pharmacodynamics of a drug is primarily commanded by the drug concentrations in the aqueous spaces of bodily tissues. However, the concentrations of the drug are not homogeneous throughout the tissues, and they rarely reflect the free drug concentration in the blood. This heterogeneity is due to differences in the blood flow fraction delivered to the tissues and membrane transporters, efflux pumps, and metabolic enzymes. The rate of drug elimination from the body (systemic elimination) depends more on the driving force of drug elimination than on the free concentration of the drug at the site from which the drug is being eliminated. In fact, the actual free drug concentration in the tissues results from the balance between the input and output rates. In the present paper, we develop a theoretical concept regarding solute partition between intravascular and extravascular spaces; discuss experimental research on aqueous/non-aqueous solute partitioning and clinical research on microdialysis; present hypotheses to predict in-vivo elimination using parameters of in-vitro metabolism.

Keywords: Solute partition, aqueous solvent, non-aqueous solvent, tissue drug concentration, tissue/blood-free drug concentration ratio, cardiac output distribution, efflux transporter, blood drug clearance, driving force concentration.

Next »
Treybal RE. Molecular diffusion in fluids. In: Mass-Transfer Operation. 3rd ed. Singapore: McGrow-Hill Book Company 1981; pp. 21-44.
Hladky SB, Barrand MA. Mechanisms of fluid movement into, through and out of the brain: Evaluation of the evidence. Fluids Barriers CNS 2014; 11(1): 26.
[] [PMID: 25678956]
Brangwynne CP, Koenderink GH, MacKintosh FC, Weitz DA. Cytoplasmic diffusion: Molecular motors mix it up. J Cell Biol 2008; 183(4): 583-7.
[] [PMID: 19001127]
Goldstein RE, van de Meent J-W. A physical perspective on cytoplasmic streaming. Interface Focus 2015; 5(4): 20150030.
[] [PMID: 26464789]
Pollard TD. Cytoplasmic movements outside the living cell. Nat Rev Mol Cell Biol 2017; 18(7): 406.
[] [PMID: 28559574]
Saffman PG, Delbrück M. Brownian motion in biological membranes. Proc Natl Acad Sci USA 1975; 72(8): 3111-3.
[] [PMID: 1059096]
Adler J, Sintorn I-M, Strand R, Parmryd I. Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous. Commun Biol 2019; 2(1): 12.
[] [PMID: 30652124]
de Haan FHN, de Vringer T, van de Waterbeemd JTM, Jansen ACA. Transport rate constants and transport rate parameters in various organic solvent-water systems. Int J Pharm 1982; 13(1): 75-87.
Fagiolino P. Multiplicative dependence of the first order rate constant and its impact on clinical pharmacokinetics and bioequivalence. Eur J Drug Metab Pharmacokinet 2004; 29(1): 43-9.
[] [PMID: 15151170]
van de Waterbeemd JTM, van Boeckel S, Jansen ACA, Gerritsma KW. Transport in QSAR II. Rate-equilibrium relationships and the interfacial transfer of drugs. Eur J Med Chem 1980; 15: 279-82.
Mudie DM, Shi Y, Ping H, Gao P, Amidon GL, Amidon GE. Mechanistic analysis of solute transport in an in vitro physiological two-phase dissolution apparatus. Biopharm Drug Dispos 2012; 33(7): 378-402.
[] [PMID: 22847296]
Fagiolino P, Wilson F, Samaniego E, Vázquez M. In vitro approach to study the influence of the cardiac output distribution on drug concentration. Eur J Drug Metab Pharmacokinet 2003; 28(2): 147-53.
[] [PMID: 12877574]
Talevi A, Bellera CL. Free drug theory. In: the ADME Encyclopedia. Cham: Springer 2021; pp. 1-6.
Fagiolino P. The influence of cardiac output distribution on the tissue/plasma drug concentration ratio. Eur J Drug Metab Pharmacokinet 2002; 27(2): 79-81.
[] [PMID: 12064375]
Ibarra M, Vázquez M, Fagiolino P. Current PBPK models: Are they predicting tissue drug concentration correctly? Drugs R D 2020; 20(4): 295-9.
[] [PMID: 33068289]
Jacob M, Chappell D, Becker BF. Regulation of blood flow and volume exchange across the microcirculation. Crit Care 2016; 20(1): 319.
[] [PMID: 27765054]
Pias SC. How does oxygen diffuse from capillaries to tissue mitochondria? Barriers and pathways. J Physiol 2021; 599(6): 1769-82.
[] [PMID: 33215707]
Lin JH. Tissue distribution and pharmacodynamics: A complicated relationship. Curr Drug Metab 2006; 7(1): 39-65.
[] [PMID: 16454692]
Poole DC, Copp SW, Ferguson SK, Musch TI. Skeletal muscle capillary function: Contemporary observations and novel hypotheses. Exp Physiol 2013; 98(12): 1645-58.
[] [PMID: 23995101]
Rutkowski JM, Swartz MA. A driving force for change: Interstitial flow as a morphoregulator. Trends Cell Biol 2007; 17(1): 44-50.
[] [PMID: 17141502]
Joukhadar C, Klein N, Frossard M, et al. Angioplasty increases target site concentrations of ciprofloxacin in patients with peripheral arterial occlusive disease. Clin Pharmacol Ther 2001; 70(6): 532-9.
[] [PMID: 11753269]
Yazdani S, Jaldin-Fincati JR, Pereira RVS, Klip A. Endothelial cell barriers: Transport of molecules between blood and tissues. Traffic 2019; 20(6): 390-403.
[] [PMID: 30950163]
MacLean DA, Bangsbo J, Saltin B. Muscle interstitial glucose and lactate levels during dynamic exercise in humans determined by microdialysis. J Appl Physiol 1999; 87(4): 1483-90.
[] [PMID: 10517782]
Zinker BA, Lacy DB, Bracy DP, Wasserman DH. Role of glucose and insulin loads to the exercising limb in increasing glucose uptake and metabolism. J Appl Physiol 1993; 74(6): 2915-21.
[] [PMID: 8365992]
Schultz TA, Lewis SB, Westbie DK, Wallin JD, Gerich JE. Glucose delivery: A modulator of glucose uptake in contracting skeletal muscle. Am J Physiol 1977; 233(6): E514-8.
[PMID: 596446]
Fagiolino P, Vázquez M, Eiraldi R. Clearance and bioavailability study through arterio-venous drug concentrations relationship. Eur J Pharm Sci 2013; 48(4-5): 825-9.
[] [PMID: 23402973]
Kaltenbach ML, Vistelle R, Hoizey G, Lamiable D, Zbierski L. Arterio-venous ethanol levels in blood and plasma after intravenous injection in rabbits. Alcohol 1998; 15(4): 319-25.
[] [PMID: 9590518]
Gourlay SG, Benowitz NL. Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray, and intravenous nicotine. Clin Pharmacol Ther 1997; 62(4): 453-63.
[] [PMID: 9357397]
Lam G, Chiou WL. Determination of the steady-state volume of distribution using arterial and venous plasma data from constant infusion studies with procainamide. J Pharm Pharmacol 1982; 34(2): 132-4.
[] [PMID: 6121879]
Wang Z, Ying Z, Bosy-Westphal A, et al. Specific metabolic rates of major organs and tissues across adulthood: Evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr 2010; 92(6): 1369-77.
[] [PMID: 20962155]
Gaffney GR, Day DK, Williamson HE. Effect of furosemide on mesenteric blood flow in the dog. Res Commun Chem Pathol Pharmacol 1978; 22(3): 605-8.
[PMID: 734239]
Iwao T, Oho K, Nakano R, et al. Effect of meal induced splanchnic arterial vasodilatation on renal arterial haemodynamics in normal subjects and patients with cirrhosis. Gut 1998; 43(6): 843-8.
[] [PMID: 9824614]
Hallbäck D-A, Hultén L, Jodal M, Lindhagen J, Lundgren O. Evidence for the existence of a countercurrent exchanger in the small intestine in man. Gastroenterology 1978; 74(4): 683-90.
[] [PMID: 631505]
O’Connor PM. Renal oxygen delivery: Matching delivery to metabolic demand. Clin Exp Pharmacol Physiol 2006; 33(10): 961-7.
[] [PMID: 17002675]
Forbes RM, Cooper AR, Mitchell HH. The composition of the adult human body as determined by chemical analysis. J Biol Chem 1953; 203(1): 359-66.
[] [PMID: 13069519]
Popovic ME, Minceva M. Thermodynamic properties of human tissues. Therm Sci 2020; 24(6 Part B): 4115-33.
Eichler H-G, Müller M. Drug distribution. The forgotten relative in clinical pharmacokinetics. Clin Pharmacokinet 1998; 34(2): 95-9.
[] [PMID: 9515183]
Fagiolino P, Eiraldi R, Vázquez M. The influence of cardiovascular physiology on dose/pharmacokinetic and pharmacokinetic/pharmacodynamic relationships. Clin Pharmacokinet 2006; 45(5): 433-48.
[] [PMID: 16640451]
Fagiolino P, Vázquez M, Eiraldi R, Maldonado C, Scaramelli A. Efflux transporter influence on drug metabolism: Theoretical approach for bioavailability and clearance prediction. Clin Pharmacokinet 2011; 50: 75-80.
[] [PMID: 21241069]
Keogh J, Hagenbuch B, Rynn C, Stieger B, Nicholls G. Membrane transporters: Fundamentals, function and their role in ADME. (Chapter 1). In: Drug Transporters: Volume 1:. Role and Importance in ADME and Drug Development 2016; pp. 1-56.
Fagiolino P, Vázquez M, Orozco-Suárez S, et al. Contribution of the antiepileptic drug administration regime in the development and/or establishment of pharmacoresistant epilepsy Pharmacoresistance in Epilepsy: From Genes and Molecules to Promising Therapies: New York, Springer Science + Business Media 2013; pp. 169-84.
Epel D, Luckenbach T, Stevenson CN, Macmanus-Spencer LA, Hamdoun A, Smital T. Efflux transporters: Newly appreciated roles in protection against pollutants. Environ Sci Technol 2008; 42(11): 3914-20.
[] [PMID: 18589945]
Harilal S, Jose J, Parambi DGT, et al. Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules. Brain Res Bull 2020; 160: 121-40.
[] [PMID: 32315731]
Hu C, Tao L, Cao X, Chen L. The solute carrier transporters and the brain: Physiological and pharmacological implications. Asian J Pharm Sci 2020; 15(2): 131-44.
[] [PMID: 32373195]
Storelli F, Billington S, Kumar AR, Unadkat JD. Abundance of P-glycoprotein and other drug transporters at the human blood-brain barrier in Alzheimer’s disease: A quantitative targeted proteomic study. Clin Pharmacol Ther 2021; 109(3): 667-75.
[] [PMID: 32885413]
Al Rihani SB, Darakjian LI, Deodhar M, Dow P, Turgeon J, Michaud V. Disease-induced modulation of drug transporters at the blood-brain barrier level. Int J Mol Sci 2021; 22(7): 3742.
[] [PMID: 33916769]
Strazielle N, Ghersi-Egea J-F. Efflux transporters in blood-brain interfaces of the developing brain. Front Neurosci 2015; 9: 21.
[] [PMID: 25698917]
Sellami M, Bragazzi NL. The effect of sport and physical activity on transport proteins: Implications for cancer prevention and control. Adv Protein Chem Struct Biol 2021; 123: 17-26.
[] [PMID: 33485483]
Quinn CJ, Gibson NM, Pfannenstiel KB, Bashore AC, Hayward R, Hydock DS. Effects of exercise on doxorubicin accumulation and multidrug resistance protein expression in striated muscle. Global J Med Res (K) 2016; 23: 11-22.
Meador BM, Huey KA. Statin-associated changes in skeletal muscle function and stress response after novel or accustomed exercise. Muscle Nerve 2011; 44(6): 882-9.
[] [PMID: 22102458]
Parker BA, Thompson PD. Effect of statins on skeletal muscle: Exercise, myopathy, and muscle outcomes. Exerc Sport Sci Rev 2012; 40(4): 188-94.
[] [PMID: 23000957]
Evans WJ, Meredith CN, Cannon JG, et al. Metabolic changes following eccentric exercise in trained and untrained men. J Appl Physiol 1986; 61(5): 1864-8.
[] [PMID: 3491061]
Thompson PD, Gadaleta PA, Yurgalevitch S, Cullinane E, Herbert PN. Effects of exercise and lovastatin on serum creatine kinase activity. Metabolism 1991; 40(12): 1333-6.
[] [PMID: 1961130]
Sallinen J, Ojanen T, Karavirta L, Ahtiainen JP, Häkkinen K. Muscle mass and strength, body composition and dietary intake in master strength athletes vs untrained men of different ages. J Sports Med Phys Fitness 2008; 48(2): 190-6.
[PMID: 18427414]
Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to muscles during exercise: A hierarchy of competing physiological needs. Physiol Rev 2015; 95(2): 549-601.
[] [PMID: 25834232]
Knauer MJ, Urquhart BL, Meyer zu Schwabedissen HE, et al. Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res 2010; 106(2): 297-306.
[] [PMID: 19940267]
Schäfer AM, Meyer Zu Schwabedissen HE, Grube M. Expression and function of organic anion transporting polypeptides in the human brain: Physiological and pharmacological implications. Pharmaceutics 2021; 13(6): 834.
[] [PMID: 34199715]
Duncan R. Epilepsy, cerebral blood flow, and cerebral metabolic rate. Cerebrovasc Brain Metab Rev 1992; 4(2): 105-21.
[PMID: 1627438]
Theodore WH, Balish M, Leiderman D, Bromfield E, Sato S, Herscovitch P. Effect of seizures on cerebral blood flow measured with 15O-H2O and positron emission tomography. Epilepsia 1996; 37(8): 796-802.
[] [PMID: 8764821]
Löscher W, Friedman A. Structural, molecular, and functional alterations of the blood-brain barrier during epileptogenesis and epilepsy: A cause, consequence, or both? Int J Mol Sci 2020; 21(2): 591.
[] [PMID: 31963328]
Grewal GK, Kukal S, Kanojia N, Saso L, Kukreti S, Kukreti R. Effect of oxidative stress on ABC transporters: Contribution to epilepsy pharmacoresistance. Molecules 2017; 22(3): 365.
[] [PMID: 28264441]
Lazarowski A, Czornyj L, Lubienieki F, Girardi E, Vazquez S, D’Giano C. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 2007; 48(s5)(Suppl. 5): 140-9.
[] [PMID: 17910594]
Czornyj L, Cáceres Guido P, Bramuglia G, Rodiño A, Feria-Romero I, Lazarowski A. High incidence of persistent subtherapeutic levels of the most common AEDs in children with epilepsy receiving polytherapy. Epilepsy Res 2018; 148: 107-14.
[] [PMID: 30279018]
Vázquez M, Fagiolino P. The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug-resistant epilepsy. Epilepsia Open 2021. ; epi4.12542.
[] [PMID: 34560816]
Hammarlund-Udenaes M. Microdialysis as an important technique in systems pharmacology—A historical and methodological review. AAPS J 2017; 19(5): 1294-303.
[] [PMID: 28762127]
Marchand S, Chauzy A, Dahyot-Fizelier C, Couet W. Microdialysis as a way to measure antibiotics concentration in tissues. Pharmacol Res 2016; 111: 201-7.
[] [PMID: 27297786]
van der Mast JE, Nijsten MW, Alffenaar JC, Touw DJ, Bult W. In vitro evaluation of an intravenous microdialysis catheter for therapeutic drug monitoring of gentamicin and vancomycin. Pharmacol Res Perspect 2019; 7(4): e00483.
[] [PMID: 31333845]
Müller M. Introduction to the Microdialysis Technology Microdialysis in Drug Development AAPS Advances in the Pharmaceutical Sciences Series. New York, NY: Springer 2013; Vol. 4.
Müller M, dela Peña A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: Distribution in tissue. Antimicrob Agents Chemother 2004; 48(5): 1441-53.
[] [PMID: 15105091]
Gonzalez D, Schmidt S, Derendorf H. Importance of relating efficacy measures to unbound drug concentrations for anti-infective agents. Clin Microbiol Rev 2013; 26(2): 274-88.
[] [PMID: 23554417]
Traunmüller F, Zeitlinger M, Zeleny P, Müller M, Joukhadar C. Pharmacokinetics of single- and multiple-dose oral clarithromycin in soft tissues determined by microdialysis. Antimicrob Agents Chemother 2007; 51(9): 3185-9.
[] [PMID: 17606673]
Langer O, Karch R, Müller U, et al. Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans. J Nucl Med 2005; 46(11): 1835-41.
[PMID: 16269597]
Müller M, Rohde B, Kovar A, Georgopoulos A, Eichler H-G, Derendorf H. Relationship between serum and free interstitial concentrations of cefodizime and cefpirome in muscle and subcutaneous adipose tissue of healthy volunteers measured by microdialysis. J Clin Pharmacol 1997; 37(12): 1108-13.
[] [PMID: 9506005]
Hansen KK, Nielsen F, Stage TB, Jørgensen U, Skov O, Rasmussen LE. Microdialysis as a tool to determine the local tissue concentration of dicloxacillin in man. Br J Clin Pharmacol 2018; 84(3): 533-41.
[] [PMID: 29105799]
Müller M, Stass H, Brunner M, Möller JG, Lackner E, Eichler HG. Penetration of moxifloxacin into peripheral compartments in humans. Antimicrob Agents Chemother 1999; 43(10): 2345-9.
[] [PMID: 10508004]
Brunner M, Hollenstein U, Delacher S, et al. Distribution and antimicrobial activity of ciprofloxacin in human soft tissues. Antimicrob Agents Chemother 1999; 43(5): 1307-9.
[] [PMID: 10223961]
Anderson C, Andersson T, Wårdell K. Changes in skin circulation after insertion of a microdialysis probe visualized by laser Doppler perfusion imaging. J Invest Dermatol 1994; 102(5): 807-11.
[] [PMID: 8176267]
Stenken JA, Church MK, Gill CA, Clough GF. How minimally invasive is microdialysis sampling? A cautionary note for cytokine collection in human skin and other clinical studies. AAPS J 2010; 12(1): 73-8.
[] [PMID: 19950008]
Turkina MV, Ghafouri N, Gerdle B, Ghafouri B. Evaluation of dynamic changes in interstitial fluid proteome following microdialysis probe insertion trauma in trapezius muscle of healthy women. Sci Rep 2017; 7(1): 43512.
[] [PMID: 28266628]
Dadson P, Ferrannini E, Landini L, et al. Fatty acid uptake and blood flow in adipose tissue compartments of morbidly obese subjects with or without type 2 diabetes: Effects of bariatric surgery. Am J Physiol Endocrinol Metab 2017; 313(2): E175-82.
[] [PMID: 28400411]
Hollenstein UM, Brunner M, Schmid R, Müller M. Soft tissue concentrations of ciprofloxacin in obese and lean subjects following weight-adjusted dosing. Int J Obes 2001; 25(3): 354-8.
[] [PMID: 11319632]
Benet LZ, Sodhi JK. Investigating the theoretical basis for in vitro – in vivo extrapolation (IVIVE) in predicting drug metabolic clearance and proposing future experimental pathways. AAPS J 2020; 22(5): 120.
[] [PMID: 32914238]
Benet LZ, Liu S, Wolfe AR. The universally unrecognized assumption in predicting drug clearance and organ extraction ratio. Clin Pharmacol Ther 2018; 103(3): 521-5.
[] [PMID: 28762489]
Bowman CM, Benet LZ. In vitro-in vivo extrapolation and hepatic clearance-dependent underprediction. J Pharm Sci 2019; 108(7): 2500-4.
[] [PMID: 30817922]
Benet LZ, Sodhi JK, Makrygiorgos G, Mesbah A. There is only one valid definition of clearance: Critical examination of clearance concepts reveals the potential for errors in clinical drug dosing decisions. AAPS J 2021; 23(3): 67.
[] [PMID: 33973074]
Hallifax D, Houston JB. Use of segregated hepatocyte scaling factors and cross-species relationships to resolve clearance dependence in the prediction of human hepatic clearance. Drug Metab Dispos 2019; 47(3): 320-7.
[] [PMID: 30610004]
Pang KS, Peng HB, Noh K. The segregated intestinal flow model (SFM) for drug absorption and drug metabolism: Implications on intestinal and liver metabolism and drug–drug interactions. Pharmaceutics 2020; 12(4): 320.
[] [PMID: 32244748]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy