Transcript
0:00What is distribution?
Part two of our introduction to ADME: distribution. Distribution is the reversible movement of a drug from the blood into the tissues and back. It decides how much of the drug reaches the tissue where it acts. In the capillaries, unbound drug crosses the vessel wall into the tissue. Four factors control distribution: blood flow, the capillary wall, binding in plasma and tissues, and barriers.
0:32Blood flow
The first factor is blood flow. Organs receive very different shares of the blood that the heart pumps each minute, the cardiac output. At rest, the liver receives about a quarter of the cardiac output, the kidneys 17 to 19 percent and the brain about 12 percent. Fat receives only 5 to 9 percent. The kidneys, the liver and the brain receive a large blood flow for their weight, so drug reaches them quickly. Fat is a large tissue with a small blood flow for its weight, so drug reaches it slowly.
1:11The capillary wall
The second factor is the capillary wall. It differs between organs. The wall is a single layer of endothelial cells. Most small drugs diffuse straight through these cells, so the type of wall matters mainly for large and water-soluble molecules. In muscle, skin and fat, the endothelial cells form a continuous wall, and small water-soluble molecules pass only through narrow gaps between the cells. In the gut and the kidney, the endothelial cells have pores called fenestrae. In the liver, the capillaries, called sinusoids, have large openings, so even large molecules reach the liver cells.
1:58Binding in plasma and tissues
The third factor is binding, in plasma and in tissues. In plasma, many drugs bind to proteins, mainly albumin and alpha-1-acid glycoprotein. The binding is reversible, and only the unbound drug can cross cell membranes and act on the target. When no transporter acts, unbound drug moves in both directions across the capillary wall until the unbound concentrations in the plasma and in the tissue are equal. Drugs also bind inside tissues. Chloroquine binds so extensively in the tissues that almost all of the chloroquine in the body is outside the plasma.
2:47The blood-brain barrier and the placenta
The fourth factor is barriers. In the brain, tight junctions close the gaps between the endothelial cells almost completely. These cells also carry P-glycoprotein, the same efflux transporter as in the gut wall. Together, they form the blood-brain barrier. Mice that lack P-glycoprotein have much higher brain concentrations of several drugs. The placenta is a second barrier. Nearly all drugs given in pregnancy cross the placenta and reach the fetus to some degree. Efflux transporters in the placenta, such as P-glycoprotein and BCRP, limit the transfer of some drugs. In perfused human placentas, blocking P-glycoprotein increased the transfer of saquinavir to the fetal side about 8 times.
3:46Summary
In summary, only unbound drug crosses cell membranes and reaches the target. Where the drug goes depends on blood flow, the capillary wall, binding in plasma and tissues, and barriers such as the blood-brain barrier and the placenta.
Sources
- Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009. PMID 19385708
- Jones H, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacometrics Syst Pharmacol. 2013. PMID 23945604
- Sarin H. Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J Angiogenes Res. 2010. PMID 20701757
- Pries AR, Kuebler WM. Normal endothelium. Handb Exp Pharmacol. 2006. PMID 16999215
- Bteich M. An overview of albumin and alpha-1-acid glycoprotein main characteristics. Heliyon. 2019. PMID 31844752
- Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov. 2010. PMID 21119731
- Gustafsson LL, Walker O, Alván G, et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol. 1983. PMID 6849784
- Schinkel AH, Smit JJ, van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994. PMID 7910522
- Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995. PMID 7560060
- Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet. 2004. PMID 15170365
- Mölsä M, Heikkinen T, Hakkola J, et al. Functional role of P-glycoprotein in the human blood-placental barrier. Clin Pharmacol Ther. 2005. PMID 16084847
- Pollex E, Lubetsky A, Koren G. The role of placental breast cancer resistance protein in the efflux of glyburide across the human placenta. Placenta. 2008. PMID 18558430
Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
