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Absorbtion:

Following dermal application (2mg/kg bw onto 2cm2application area) MDA was well absorbed in rats (50% in 96h), though to a minor extend in guinea pigs (29% in 96h) and monkeys (21% in 168h) (El-Hawari et al., 1986). In these experiments, significant amounts of MDA were recovered in the skin of the application area at the end of the observation period (26% in rats and 41% in guinea pigs).

From the percental reduction of total absorbed radioactivity with increased test doses (54% with 0.4mg/rat to 6% with 4mg/rat, 17% with 1mg/guinea pig to 7% with 10mg/guinea pig), a saturable transport process can be anticipated.

 

In an occlusive in vitro assay dose-levels of 17.7-40.6 µg/cm2were applied to isolated human skin or 20.1-34.4 µg/cm2to isolated rat skin, respectively. Absorption rates of 33% with isolated human skin and 13% with isolated rat skin were observed during an observation period of 72h (Hotchkiss et al., 1993). These rates decreased significantly when the application area was not occluded. Like in the in vivo assay major amounts of radioactivity were recovered in the skin surface (25% in rat skin, 17% in human skin).

Distribution:

Following dermal and intravenous application in rats and guinea pigs (El-Hawari et al., 1986) and intraperitoneal application in rats and rabbits (Morgott et al., 1984), MDA was readily distributed. 

The residual radioactivity in the organs following a single i.p. dose of 14C-MDA tends to localize in the liver, kidney, spleen and thyroid at both 24 and 96 hours (Morgott et al., 1984). In addition a significant quantity of radioactivity was detected in plasma and red blood cells. No evidence for accumulation in the body was found, since tissue contents of radioactivity markedly decreased between 24 and 96h after application of the test substance.

Similar distribution patterns were reported following dermal and intravenous application in rats and guinea pigs (El-Hawari et al., 1986), again the liver seems to be the major tissue for recovery of radioactivity.

 

Excretion:

The fate of MDA seems to vary inbetween different species. Though both, rats and rabbits eliminate at least 90% of an i.p. dose within four days, the primary route of excretion is different for each. Rats excrete approximately 55% of the recovered radioactivity into the feces, whereas fast and slow acetylator rabbits excrete about 80% of the applied compound into the urine and less than 25% into the feces (Morgott et al., 1984). Since the compound was administered by the intraperitoneal route, the amount of fecal radioactivity provided an indication of bilary excretion. These differences in elimination pattern may also be reflected in the resistance of the rabbit to MDA-induced liver damage.

Similar excretion patterns were observed in a comparative study with rats, guinea pigs and monkeys following an intravenous injection (2mg/kg bw) of 14C-MDA. However, for rats significantly higher urinary excretion 96h following i.v. dosing (67% in urine and 30.7% in feces) was reported compared to i.p. dosing in the study of Margott et al. (1984).

For guinea pigs fecal excretion averaged 56.5% and urinary excretion 35%, whereas in monkeys excretion of 14C-MDA occurred primarily in the urine (84.3%) and to a lesser extent in the feces (9.8%). Peak eliminations occurred within 24h in rats and guinea pigs and within 12h following application in monkeys (El-Hawari et al., 1986).

In the same study elimination following dermal applications of low (2mg/kg bw) and a high doses (20mg/kg bw) were described in rats, guinea pigs and monkeys. Fecal/urinary excretion of the applied dose 96h following application averaged 10%/43% for rats and 17%/10% for guinea pigs. In monkeys 1.4% and 19% were detected in feces or urine 168 h following dosing, respectively. The percentage of radioactivity recovered in excreta decreases significantly in the high dose level, again describing a saturable kinetic (El-Hawari et al., 1986).

The total recovery of radioactivity from the rat and slow acetylator rabbit is about 10% less than the recovery from the fast acetylator rabbit. This difference in recovery between fast and slow acetylating rabbits is associated with the greater fecal excretion by the fast acetylator rabbit. 

In a mouse study the time course of elimination following a single intraperitoneal application of 14C-MDA was determined. The elimination rate Kelwas calculated as 0.22 h-1, resulting in a half-life (t1/2) of 3.2h (Tortoreto et al., 1983). Unfortunately no raw data is provided to comprehensively reproduce calculations.

Metabolism:

Although differences in the quantitative aspects of metabolism remain unelucidated, the in vivo biotransformation pathways of MDA involve N-acetylation reactions as well as an oxidation of the central C-atom and conjugation to glucuronides and sulfates. The N-acetylation apparently represents the major detoxification pathway, whereas the N-hydroxylation additionally being supposed from in vitro studies may lead to potentially toxic intermediates.

 

Following oral application of MDA to Sprague-Dawley rats (50 mg/kg bw) N-acetyl-MDA has been shown being the major metabolite (Tanaka et al., 1985). Minor amounts of N,N´-diacetyl-MDA and free MDA were also detected in the urine. The total amount of metabolites added to 3% of the applied dose and was nearly entirely excreted during the 72h observation period.

 

In a more elaborate analytical assay at least 17 urinary metabolites were characterized upon a single i.p. administration of MDA to Sprague-Dawley rats (30 mg/kg bw) (Morgott, 1984). Mainly, the following acetylated metabolites have been identified: N-acetyl-MDA, N,N´-diacetyl-MDA, N,N´-diacetyl-3-hydroxy-MDA, N-acetyl-4,4' -diaminobenzophenone, and N,N´-diacetyl-4,4´-diamino-benzhydrol.

The study was performed in rats and rabbits, showing that at least 50% of the urinary radioactivity in both species is composed of freely extractable metabolites, which are not glucuronide or sulfate conjugates. Furthermore, O-glucuronide and O-sulfate conjugates only constituted about 3% of total extractable radioactivity, which is approximately 70% in the rat and 80% in the rabbit. However, unlike in the rat, a relatively high percentage of N-glucuronide metabolites were found in rabbit urine.

From the biotransformation products identified in the urine of rats and rabbits it can be seen, that the major biotransformation reactions are N-acetylation and bridge oxidation.

The major urinary metabolite excreted by the rat was N,N´-diacetyl-4,4´-diaminobenzhydrol, which accounted for approximately 40% of the radioactivity in hydrolyzed specimens. The main metabolite in hydrolysed urine of fast and slow acetylator rabbits was the parent compound MDA, which accounted for about 45% and 65% of the radioactivity in hydrolyzed urine specimens, respectively.

The overall metabolism of MDAwas extensive compared to the rabbit, where minimal biotransformation occurred.

 

In vitro metabolism of MDA was investigated using rabbit liver microsomes (Kajbaf et al., 1992) in which only CYP-dependent metabolism can be observed. The following three metabolites were detected: azo-MDA, azoxy-MDA, and nitroso-MDA (4-nitroso-4'-aminodiphenylmethane). The azo- and azoxy-compounds were formed enzymatically, whereas the nitroso-compound may have been formed via a non-enzymatic process. The hydroxylamine of MDA was not detected in this study. However, its initial formation has to be supposed as prerequisite for the formation of the dimeric MDA metabolites azo- and azoxy-MDA.

 

Binding to macromolecules:

24 hours after a single oral or i.p. administration of MDA a dose dependent increase of hemoglobin-adducts could be detected in the rat ( Bailey at al., 1990; ). Predominanty, the monoacetylated MDA seems to react with hemoglobin. In contrast to these results Neumann et al. (1993) found more hemoglobin-adducts derived from the parent compound than from N-acetyl-MDA after single oral administration of MDA.

Formation of DNA adducts was reported from livers of rats after i.p. application of radiolabeled MDA (Schütze et al. 1996).