Pharmacokinetics
Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly. Peak plasma concentrations (Cmax) are reached within one to three hours of taking immediate-release metformin and four to eight hours with extended-release formulations. The plasma protein binding of metformin is negligible, as reflected by its very high apparent volume of distribution (300–1000 L after a single dose). Steady state is usually reached in one or two days.
Metformin has acid dissociation constant values (pKa) of 2.8 and 11.5 and, therefore, exists very largely as the hydrophilic cationic species at physiological pH values. The metformin acid dissociation constant values (pKa) make metformin a stronger base than most other basic drugs with less than 0.01% unionized in blood. Furthermore, the lipid solubility of the unionized species is slight as shown by its low logP value of -1.43. These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of metformin through cell membranes is unlikely. The logP of metformin is less than that of phenformin (-0.84) because two methyl substituents on metformin impart lesser lipophilicity than the larger phenylethyl side chain in phenformin. More lipophilic derivatives of metformin are presently being investigated with the aim of producing prodrugs with better oral absorption than metformin itself.
Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; metformin is undetectable in blood plasma within 24 hours of a single oral dose. The average elimination half-life in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of non-diabetic people).
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