Disposition of 14C-α-cyclodextrin in germ-free and conventional rats

Abstract

The absorption, disposition, metabolism, and excretion of uniformly (14)C-labeled alpha-cyclodextrin ((14)C-alpha-CD) was examined in four separate experiments with Wistar rats. In Experiment 1, (14)C-alpha-CD (25 microCi, 50 mg/kg bw) was administered intravenously to four male and four female conventional rats. In Experiment 2, (14)C-alpha-CD (25 microCi, 200 mg/kg bw) was given by gavage to four male and four female germ-free rats. In Experiments 3 and 4, (14)C-alpha-CD was given to groups of four male and four female conventional rats by gavage at different dose levels (100 microCi, 200 mg/kg bw; 25 microCi, 200 and 100 mg/kg bw). In all experiments, (14)C was measured in respiratory CO(2), urine, and feces over periods of 24-48 h, and in the contents of the gastrointestinal tract, blood, main organs, and residual carcass at termination of the experiments. The chemical identity of the (14)C-labeled compounds was examined by HPLC in blood (Experiment 1), urine (Experiments 1-4), feces (Experiments 2-4), and samples of intestinal contents (Experiments 2 and 4). Recovered (14)C was expressed as percentage of the administered dose. Experiment 1 showed that intravenously administered alpha-CD is excreted rapidly with urine. During the first 2h after dosing, plasma (14)C levels decreased rapidly (t(1/2), 26 and 21 min in male and female rats, respectively). About 13% of the administered (14)C dose (range 4.6-30.6) was detected in the feces, respiratory CO(2), organs, and carcass at the end of the experiment, i.e., 24 h after dosing. The presence of about 1.9% in the intestinal contents and feces suggests that a certain fraction of systemic alpha-CD is eliminated with the bile or saliva. Conclusive evidence, either positive or negative, for a hydrolysis and further metabolism of a small fraction of the administered alpha-CD by the enzymes of the mammalian body could not be gained from this experiment. Upon oral administration of (14)C-alpha-CD to germ-free rats (Experiment 2), about 1.3% of the label expired as CO(2) within 24 h. In the urine collected from 0 to 8 h after dosing, (14)C-alpha-CD was the only radiolabeled compound detected. The amounts of alpha-CD detected in the urine suggest that on average about 1% of an oral dose is absorbed in rats during small-intestinal passage. In conventional rats (Experiments 3 and 4), a delayed appearance of respiratory (14)CO(2) was observed which is attributed to the non-digestibility of alpha-CD and its subsequent microbial fermentation in the cecum and colon. In the urine collected at 4 h after dosing, a small amount of unchanged (14)C-alpha-CD was detected which confirms that about 1% of the ingested alpha-CD is absorbed intact and is excreted via the kidneys. No (14)C-alpha-CD was found in the feces. It is concluded from the data that ingested (14)C-alpha-CD is not digested in the small intestine of rats but is fermented completely by the intestinal microbiota to absorbable short-chain fatty acids. Therefore, the metabolism of alpha-CD resembles closely that of resist...

Sugammadex is cleared rapidly and primarily unchanged via renal excretion

“…C γ-cyclodextrin given i.v. to rat [14,15] excretion into the feces has also been demonstrated to be a minor route of excretion (3-8% of the dose); however, as shown in the current study, this route is not applicable for sugammadex in man.…”

“…Therefore M9 can be excluded as a metabolite, and most likely this peak relates to a minor impurity in the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 C γ-cyclodextrin given i.v. to rat [14,15] excretion into the feces has also been demonstrated to be a minor route of excretion (3-8% of the dose); however, as shown in the current study, this route is not applicable for sugammadex in man.…”

“…There may be many causes of incomplete recovery of the radiolabel in mass balance trials (such as technical limitations and tissue retention), and it is actually rare for the mass balance in radiolabeled excretion studies to truly achieve 100% recovery [16]. 16 The minimal role of metabolism in the clearance of sugammadex is fully in line with the excretion profile of other cyclodextrins, which has been noted to be almost entirely renal [14,15,17,18], particularly in man. Subsequent profiling for metabolites in urine and plasma samples demonstrated that the major part of total radioactivity could be attributed to the parent compound, sugammadex (data on file).…”

Cyclodextrins

“…This may be related to its ability to interact with cellular membranes and its hemolytic activity (Thompson, 1997). The total plasma clearance for HP-β-CD and SBE-β-CD in all species tested is similar to the glomerular filtration rate of individual species (Davies and Morris, 1993), and essentially 100% of a given dose is recovered in the urine within 6 to 12 hours following IV administration (Zhou et al, 1998;CyDex, unpublished) Following absorption, CDs distribute to various tissues including the kidney, urinary bladder, liver, adrenal gland, and others (Gerloczy et al, 1990;Monbaliu et al, 1990;Antlsperger and Schmid, 1996;Kubota et al, 1996;De Bie et al, 1998;Van Ommen et al, 2004). The kidney has the highest level of CDs of all tissues.…”

Dose-Dependent Inhibition of the Post-Prandial Glycaemic Response to a Standard Carbohydrate Meal following Incorporation of Alpha-Cyclodextrin

“…There are three types of CDs, each containing a different number of glucosyl residues; ␣ -CD consists of 6 glucose units, while ␤ -CD and ␥ -CD consist of 7 and 8 glucose units, respectively [14] . The ␣ -and ␤ -CDs are resistant to hydrolysis by acids and human salivary and pancreatic amylases [15] , and are not digested to any signifi cant degree in the small intestine [16] . Since ␣ -CD is essentially not digested in the small intestine, it is by defi nition a dietary fi bre, or more precisely, a soluble, fermentable dietary fi bre.…”