Clinical pharmacokinetics of metformin

Graham, Garry G., Punt, Jeroen, Arora, Manit, Day, Richard O., Doogue, Matthew P., Duong, Janna K., Furlong, Timothy J., Greenfield, Jerry R., Greenup, Louise C., Kirkpatrick, Carl M., Ray, John E., Timmins, Peter and Williams, Kenneth M. (2011) Clinical pharmacokinetics of metformin. Clinical Pharmacokinetics, 50 2: 81-98. doi:10.2165/11534750-000000000-00000

Author Graham, Garry G.
Punt, Jeroen
Arora, Manit
Day, Richard O.
Doogue, Matthew P.
Duong, Janna K.
Furlong, Timothy J.
Greenfield, Jerry R.
Greenup, Louise C.
Kirkpatrick, Carl M.
Ray, John E.
Timmins, Peter
Williams, Kenneth M.
Title Clinical pharmacokinetics of metformin
Journal name Clinical Pharmacokinetics   Check publisher's open access policy
ISSN 0312-5963
Publication date 2011-02-01
Sub-type Article (original research)
DOI 10.2165/11534750-000000000-00000
Open Access Status Not yet assessed
Volume 50
Issue 2
Start page 81
End page 98
Total pages 18
Place of publication New York, NY, United States
Publisher ADIS Press International
Language eng
Formatted abstract
Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion throughcell membranes should be very limited. The mean ±-SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t1/2) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CLR) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130mL/min and 1140 ± 330mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CLR and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CLCR). As the CLR and CL/F decrease approximately in proportion to CLCR, the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CLCR. The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin. Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5mg/L in order to minimize the development of this adverse effect.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Pharmacy Publications
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Created: Tue, 15 Feb 2011, 22:49:09 EST by Charna Kovacevic on behalf of School of Pharmacy