Toxicology of Biguanides
The use of biguanides as oral antidiabetic agents has elicited considerable problems due to their lack of sufficient tolerability. The first derivative, phenylethylbiguanide (phenformin), was given marketing approval in the United States in 1957. Due to t
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Toxicology of Biguanides F. SCHMIDT, F. HARTIG, W. REBEL, and P. OCHLICH
A. Introduction The use of biguanides as oral antidiabetic agents has elicited considerable problems due to their lack of sufficient tolerability. The first derivative, phenylethylbiguanide (phenformin), was given marketing approval in the United States in 1957. Due to the serious side effects, however, the compound was withdrawn from the market in the United States and the major European countries about 20 years later. Similar problems occurred with Nbutylbiguanide (buformin), which was given market approval in Europe in 1960. N-Dimethylbiguanide (metformin) is a cIearly less active agent from this dass, but it is the only derivative which is approved in a number of countries incIuding the United States for therapeutic application. Diabetes research into guanidine derivatives focused from 1956 nearly exdusively on biguanides. Analogues of special interest are as folIows: 1. NI,n-Amylbiguanide (DBB, AB4)
2. 3. 4. 5.
N]-Iso-amylbiguanide N]-Phenethylbiguanide (phenformin, DBI) N]n-Butylbiguanide (buformin) N] ,N]-Dimethylbiguanide (metformin, LA6023)
While the first two substances had no therapeutic impact as antidiabetic agents, phenformin, metformin and buformin have been investigated in more detail.
B. General Pharmacology and Toxicology Biguanides exert markedly different hypoglycemic activlties in various animal species, as shown in Table 1. The reason for these differences may be, on the one hand, a different species-dependent pattern of hormones and enzymes which are involved in the maintenance of blood glucose homoeostasis. On the other hand, there are indications of distinct differences between various animal species in the pharmacokinetics and also the route of administration of biguanides. Very high doses of biguanides have to be administered orally, in contrast to parenteral injection, to achieve blood glucose lowering effects, e.g., the intestinal absorption rate of phenformin is J. Kuhlmann et al. (eds.), Oral Antidiabetics © Springer-Verlag Berlin Heidelberg 1996
F. SCHMlDT et al.
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Table 1. Blood glucose effects in different animal species (minimal blood glucose decrease of 20%) after parenteral administration (modified from BECKMANN 1(71)
Species
Administration
Phenformin (mg/kg)
Buformin (mg/kg)
Mouse
s.c. I. v. s.c. I. v. i.p. S.c. I. v. s.c.
200 20 75
100
Rat Guinea pig Dog Monkey
60
30~ 75
15 25
25 25 25
Metformin (mg/kg) ]()O
200 350
WO
6
Table 2. Minimal active doses of biguanides in fasted guinea pigs after s.c. dosage and therapeutic doses in type 2 diabetics during treatment (daily dose for effcctive treatment)
Compound Phenformin Buformin Metformin
Guinea pigs (s.c.) (mg/kg) 7.5~
10
20 75
Humans (type 2 diabctics) (mg/patient) 50~
100
]()O~ 200
500~ 2000
rather low and its metabolism to parahydroxy-phenformin occurs fairly rapidly. Thus it is small wonder that no hypoglycemic effect was seen in healthy rats but only in partly nephrectomized rats (HRSTKA et al. 1977b). The most fav
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