Acarbose

In all species tested, acarbose exerts its activity in the intestinal tract. The action of acarbose is based on the competitive inhibition of intestinal enzymes (α-glucosidases) involved in the degradation of disaccharides, oligosaccharides, and polysaccharides. This leads to a dose-dependent delay in the digestion of these carbohydrates. Glucose derived from these carbohydrates is released and taken up into the blood more slowly. In this way, acarbose reduces the postprandial rise in blood glucose, thus reducing blood glucose fluctuations.

Following administration, only 1-2% of the active inhibitor is absorbed.

The pharmacokinetics of acarbose were investigated after oral administration of the ¹⁴C-labelled substance (200mg) to healthy volunteers. On average, 35% of the total radioactivity (sum of the inhibitory substance and any degradation products) was excreted by the kidneys within 96 h. The proportion of inhibitory substance excreted in the urine was 1.7% of the administered dose. 50% of the activity was eliminated within 96 hours in the faeces. The course of the total radioactivity concentration in plasma was comprised of two peaks. The first peak, with an average acarbose-equivalent concentration of 52.2 ± 15.7μg/l after 1.1 ± 0.3 h, is in agreement with corresponding data for the concentration course of the inhibitor substance (49.5 ± 26.9μg/l after 2.1 ± 1.6 h). The second peak is on average 586.3 ± 282.7μg/l and is reached after 20.7 ± 5.2 h. The second, higher peak is due to the absorption of bacterial degradation products from distal parts of the intestine. In contrast to the total radioactivity, the maximum plasma concentrations of the inhibitory substance are lower by a factor of 10-20. The plasma elimination half-lives of the inhibitory substance are 3.7 ± 2.7 h for the distribution phase and 9.6 ± 4.4 h for the elimination phase.

A relative volume of distribution of 0.32 l/kg body-weight has been calculated in healthy volunteers from the concentration course in the plasma.

Acute toxicity

LD₅₀ studies were performed in mice, rats and dogs. Oral LD₅₀ values were estimated to be >10 g/kg body-weight. Intravenous LD₅₀ values ranged from 3.8 g/kg (dog) to 7.7 g/kg (mouse).

Sub-chronic toxicity

Three month studies have been conducted in rats and dogs in which acarbose was administered orally by gavage.

In rats, daily doses of up to 450 mg/kg body-weight were tolerated without drug-related toxicity.

In the dog study, daily doses of 50-450 mg/kg were associated with decreases in body-weight. This occurred because dosing of the animals took place shortly before the feed was administered, resulting in the presence of acarbose in the gastro-intestinal tract at the time of feeding. The pharmacodynamic action of acarbose led to a reduced availability of carbohydrate from the feed, and hence to weight loss in the animals. A greater time interval between dosing and feeding in the rat study resulted in most of the drug being eliminated prior to feed intake, and hence no effect on body-weight development was observed.

Owing to a shift in the intestinal α-amylase synthesis feedback mechanism a reduction in serum α-amylase activity was also observed in the dog study. Increases in blood urea concentrations in acarbose-treated dogs also occurred, probably as a result of increased catabolic metabolism associated with the weight loss.

Chronic toxicity

In rats treated for one year with up to 4500 ppm acarbose in their feed, no drug-related toxicity was observed. In dogs, also treated for one year with daily doses of up to 400 mg/kg by gavage, a pronounced reduction in body-weight development was observed, as seen in the sub-chronic study. Again this effect was due to an excessive pharmacodynamic activity of acarbose and was reversed by increasing the quantity of feed.

Carcinogenicity studies

In a study in which Sprague-Dawley rats received up to 4500 ppm acarbose in their feed for 24-26 months, malnutrition was observed in animals receiving the drug substance. A dose-dependent increase in tumours of the renal parenchyma (adenoma, hypernephroid carcinoma) was also observed against a background of a decrease in the overall tumour rate. When this study was repeated, an increase in benign tumours of testicular Leydig cells was also observed. Owing to the malnutrition and excessive decrease in bodyweight gain these studies were considered inadequate to assess the carcinogenic potential of acarbose.

In further studies with Sprague-Dawley rats in which the malnutrition and glucose deprivation were avoided by either dietary glucose supplementation or administration of acarbose by gavage, no drug-related increases in the incidences of renal or Leydig cell tumours were observed.

In an additional study using Wistar rats and doses of up to 4500 ppm acarbose in the feed, neither drug-induced malnutrition nor changes in the tumour profile occurred. Tumour incidences were also unaffected in hamsters receiving up to 4000 ppm acarbose in the feed for 80 weeks (with and without dietary glucose supplementation).

Reproductive toxicity

There was no evidence of a teratogenic effect of acarbose in studies with oral doses of up to 480 mg/kg/day in rats and rabbits.

In rats no impairment of fertility was observed in males or females at doses of up to 540 mg/kg/day. The oral administration of up to 540 mg/kg/day to rats during foetal development and lactation had no effect on parturition or on the young.

Mutagenicity

The results of a number of mutagenicity studies show no evidence of a genotoxic potential of acarbose.