In this second blog dedicated to pharmacokinetics, we will discuss drug distribution.

Drug distribution is where the drug travels as it moves through the bloodstream into various tissues, organs, etc. Drugs vary widely in their degree or volume of distribution (Vd). Medications with a low volume of distribution tend to stay primarily in body water (hydrophilic) while those that have higher volumes of distribution go into tissues throughout the body (lipophilic). Understanding these characteristics give great insight into both therapeutic as well as side effect profiles. Let's do a few examples to highlight these points.

1. Aminoglycosides- These antibiotics are used primarily in the management of severe gram-negative infections. Their overall volume of distribution is very low, around 0.25L/kg on average. Therefore these don't penetrate lung, central nervous system (CNS), or other tissues very well but have excellent urinary excretion because they pretty much stay in body water. This makes them very useful for treating urinary tract infections.
2. Tigecycline (Tygacil)- This antibiotic however has a very high volume of distribution (7-9 L/kg) and therefore penetrates nearly every tissue outside of the bloodstream. Very little of the drug remains in the bloodstream, making it not idea for treating bloodstream infections. Tetracyclines in general have high volumes of distribution which explain some of their known bone penetration, including permanent tooth discoloration in kids < 8 years of age (generally avoid).
3. Linezolid (Zyvox)- While most antibiotics do not penetrate the CNS well, linezolid does get decent penetration. This explains very well two important characteristics. First, CNS side effects are very common with linezolid including headache and dizziness that can lead to discontinuation. Second, linezolid exhibits weak monoamine oxidase inhibition activity, which can in rare circumstances lead to serotonin overload when administered with other serotonergic agents.
4. Amiodarone (Cordarone)- This antiarrythmic has a volume of distribution of ~65L/kg. Wow! This explains why the adverse effect profile is widespread with thyroid, ocular, liver, lung, and many more tissues with significant levels. Hence this drug requires frequent monitoring of many different labs to ensure safety. The half-life due to accumulation in these tissues is several MONTHS and therefore discontinuation is imperative as quick as possible as it will take a while to leave the body.

A good (but not 100%) rule of thumb is that for antibiotics that have a target site that is intracellular (e.g. the ribosome), their volume of distribution will be higher than other agents. These drugs have to pass through a lipid layer of the bacteria to get to the target site of action and thus makes sense that they would be more lipophilic with higher Vd.

Our next post will be on the "M" of ADME of pharmacokinetics-Metabolism. Check out our videos here at TeachMePharm.com as we integrate these principles within individual drug therapies.

Chris