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A primary question for any drug is the value of its serum concentration. What is not commonly considered is the relationship between this value and the drug concentration at the physiological target site. In the case of metformin, the issue is in some ways simple: metformin is water soluble and has negligible binding to serum proteins. It is not converted to other compounds, but excreted unchanged by the kidney. Yet, the volume of distribution is very high: above 500 l. This is because its serum concentration is low (micromolar) and yet the dosing is very high (up to nearly gram amounts). The precise volume of distribution value is complicated by the fact that serum levels do not reach a simple steady state but rather sharply descend with time. This has been described as “following a multiphasic pattern”.
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