Adding on to some of the good comments here, many drugs have physical properties that cause them to distribute in body tissues beyond the blood. For instance, when we give patients oral antibiotics for infections of a specific organ (prostatitis, for example), we need to choose an antibiotic that has good penetration to the prostate. Or good bone penetration for osteomyelitis. If a drug is extremely lipophilic and is given to an obese person, the volume of distribution can be effectively limitless and difficult to ascertain, because it distributes beyond the blood and into the fat tissue. The log P value of a drug will give us a clue to how widely the drug distributes, but we would need multiple samples to truly understand the kinetics how the drug is eliminated in a specific patient.

There are also special circumstances that complicate this “2-compartment pharmacokinetics” process. When we give a cancer patient high dose methotrexate infusions, the drug will distribute into any excess body fluid in the patient, like edema. The body will then clear the blood of the drug, but the methotrexate-laden body fluid will effectively re-bolus the patient with the drug and raise their blood levels again, long after we’ve stopped the infusion.