Half life of Nitrofurantoin

Both wikipedia and Toxnet list the half-life of Nitrofurantoin as 20-60 minutes in the blood plasma. Can anyone explain how this is so short, especially for an antibiotic, and how it still has time to be effective.

• This question may be better off on Biology.SE – JSCoder says Reinstate Monica Apr 28 '18 at 15:12
• Nah. We're just talking pharmacokinetics. – Zhe Apr 29 '18 at 12:27

Mechanism of action: Nitrofurantoin is concentrated in the urine, leading to higher and more effective levels in the urinary tract than in other tissues or compartments. With a $\pu{100 mg}$ oral dose, plasma levels are typically less than $\pu{1 \mu g/ml}$ while in the urine it reaches $\pu{200 \mu g/ml}$. The mechanism of action is unique and complex. The drug works by damaging bacterial DNA, since its reduced form is highly reactive. This is made possible by the rapid reduction of nitrofurantoin inside the bacterial cell by flavoproteins (nitrofuran reductase) to multiple reactive intermediates that attack ribosomal proteins, DNA,[38] respiration, pyruvate metabolism and other macromolecules within the cell. Nitrofurantoin exerts greater effects on bacterial cells than mammalian cells because bacterial cells activate the drug more rapidly. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal activity. The broad mechanism of action for this drug likely is responsible for the low development of resistance to its effects, as the drug affects many different processes important to the bacterial cell.

High availability of nitrofurantoin in the urine ($\pu{200 \mu g/ml}$) compared to that in plasma ($\pu{1 \mu g/ml}$) is due to its high solubility in the urine. At this concentration, it exceeds the requirement for minimum inhibitory concentration for bacteria ($\pu{32 \mu g/ml}$), and as a result, nitrofurantoin becomes bactericidal in urine at therapeutical doses ($\pu{100 mg/capsule}$). Keep in mind that reduced nitrofurantoin (its metabolite by nitrofuran reductase) is much more reactive than nitrofurantoin, thus shorter half-life make it highly lethal to bacteria.

Why is it effective with such a low half-life in the blood?

First, we need to see what it is used for. This drug is primarily used to treat urinary tract infections (UTI). Therefore, it needs to be delivered to the urinary tract. The short half-life is a benefit because the drug gets concentrated in the patient’s urine, which kills bacteria in the urinary tract.

How is it metabolized?

Bioavailability is 80%, with roughly 25% of nitrofurantoin excreted in the urine unchanged. Except in patients with severe renal failure, serum concentrations are almost undetectable, with peak levels of 1 µg/mL. This is because of destruction of nitrofurantoin in the tissues and, in particular, a very rapid renal elimination by glomerular filtration (20%) and tubular secretion, resulting in a serum half-life of only 20 minutes in patients with normal renal function.