In March 2019, the journal Medicinal Research Reviews published a review* summarizing all available data on the pharmacokinetics of bacteriophages. The review's author, Krystyna Dąbrowska, is a researcher at the Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences, a global center for research into bacteriophages as therapeutic agents. Here are the author's key findings.

The ability of bacteriophages to penetrate human tissues and organs depends largely on the route of administration of the phage preparation. Oral administration ensures effective delivery of phages to the gastrointestinal tract (GIT), while the efficiency of phage transit through the intestines (excretion in feces) is dose-dependent. Phage transit through the GIT also depends on the species and age of the animal (younger animals excrete more phages in feces), which is likely explained by the peculiarities of digestive physiology, in particular the characteristic intestinal microbiome and digestive juices.

Interestingly, phages do not appear to be particularly sensitive to gastric acid. This is supported by observations that neutralization of the acid during administration of phage preparations does not significantly improve phage passage through the stomach. This contradicts generally accepted opinion and may be due to the following: (1) phage sensitivity to pH varies, and many phages are relatively resistant to acid destruction; (2) in vivo and in vitro conditions differ, and while phages typically exhibit acid sensitivity in vitro experiments, in vivo conditions are influenced by, for example, the ionic composition of the medium and the large number of organic macromolecules; (3) phage proliferation in the lower gastrointestinal tract can compensate for their loss in the stomach. The latter is consistent with the fact that the presence of target bacteria in the gastrointestinal tract significantly increases the number of phages excreted in the feces. This indicator was successfully increased by artificially introducing target bacteria into the gastrointestinal tract. It appears that phage proliferation in the intestine is a decisive factor influencing the rate of their excretion in feces.

Oral administration of phage preparations is well suited for delivering phages to the gastrointestinal tract, but less so for systemic action. This means that their absorption in the gastrointestinal tract is limited, although it correlates with the dose: the more phages ingested, the greater the chance of their successful dissemination throughout the body's tissues. Gastric acid neutralizers do not affect this process. Systemic penetration of phages through the respiratory tract is possible, but ineffective. The most effective methods for systemic phage administration are injections (IM, IV, or intraperitoneal), which allow phages to spread throughout the body within minutes.

Systemic administration allows phages to reach many (potentially any) tissues and organs: this has been demonstrated, in particular, for skeletal muscle, heart, thymus, bone marrow, kidneys, bladder, salivary glands and saliva, and even the brain, although these organs do not accumulate phages. Phage penetration into the lungs and their "re-penetration" into the intestinal lumen is also possible, but ineffective. No experiments have yet been conducted to evaluate phage penetration into such important therapeutic targets as joints, bones, pancreas, eyes, etc.

Phage accumulation was observed in the spleen, liver, and lymph nodes—organs involved in the development of a nonspecific immune response. Phage clearance is primarily associated with phagocytosis of phage particles in the liver and, to a lesser extent, in the spleen. Phage excretion in urine is insignificant, possibly due to the large size of phage particles. Thus, the immune system plays a key role in phage clearance even in cases where a specific immune response to the phage has not developed. Phage titers in the blood shortly after intravenous administration (up to 30 minutes) are usually lower than expected due to dilution in the total blood volume. This indicates that phage uptake by the reticuloendothelial system occurs very rapidly. Later, the rate of phage clearance declines.

* Dąbrowska K. Phage therapy: What factors shape phage pharmacokinetics and bioavailability? Systematic and critical review. Med Res Rev. First published: March 19, 2019. https://doi.org/10.1002/med.21572