Metformin kinetics in healthy subjects and in patients with diabetes mellitus
G T Tucker, C Casey, P J Phillips, H Connor, J D Ward, H F Woods, G T Tucker, C Casey, P J Phillips, H Connor, J D Ward, H F Woods
Abstract
1 The kinetics of metformin were studied after i.v. and oral administration in four healthy subjects and after oral administration in twelve maturity onset (Type II) diabetic patients.
2 After i.v. administration most of the dose was rapidly eliminated but with a mean `terminal' T1/2 of 4 h measured up to 12 h in plasma and of 16 h measured up to 60 h from the urinary excretion rate. On average, 80% of the dose was recovered as unchanged drug in the urine with none detected in the faeces.
3 After single oral doses (0.5 and 1.5 g), maximum plasma concentrations and urinary excretion rates were observed at about 2 h with urinary recoveries of unchanged drug of 35-50% and faecal recoveries of about 30%. Urinary recoveries were significantly lower after the higher dose. Absolute oral bioavailability was 50-60% of the dose.
4 Deconvolution analysis showed that after a short lag-time, the available oral dose was absorbed at an exponential rate over about 6 h. Implications for the design of prolonged release dosage forms are discussed.
5 Plasma metformin concentrations measured throughout the seventh and fourteenth days of continuous 0.5 g twice daily treatment were accurately predicted from single dose data, although a discrepancy between observed and predicted trough levels reflected the existence of a slow elimination phase. Implications of the latter for a gradual accumulation of metformin in peripheral tissues and a possible association with lactic acidosis are discussed.
6 Renal clearance of metformin was highly correlated with creatinine clearance. However, a weaker relationship between total oral clearance of the drug and creatinine clearance suggests that the latter may not always be a reliable indicator of potential metformin accumulation owing to variability in absorption and possibly non-renal clearance of the drug,
References
- Br Med J. 1978 Aug 12;2(6135):464-6
- Clin Pharmacol Ther. 1978 Dec;24(6):683-93
- Wien Klin Wochenschr. 1979 Jan 19;91(2):59-65
- Comput Biomed Res. 1978 Aug;11(4):345-61
- Eur J Clin Pharmacol. 1979 Sep;16(3):195-202
- J Pharmacokinet Biopharm. 1980 Feb;8(1):99-104
- Br J Clin Pharmacol. 1978 Aug;6(2):183-5
- Diabetologia. 1969 Oct;5(5):318-24
- J Pharmacokinet Biopharm. 1974 Apr;2(2):123-48
- Br Med J. 1977 Jan 22;1(6055):234
- Diabetologia. 1977 May;13(3):211-7
- J Pharm Sci. 1978 May;67(5):663-5
- J Pharm Sci. 1968 Jun;57(6):918-28
Source: PubMed