Biotransformation of 1,1,1,3,3-Pentafluoropropane (HFC-245fa)

Abstract

1,1,1,3,3-Pentafluoropropane (HFC-245fa) is being developed as a CFC substitute. 1,1,1,3,3-Pentafluoropropane has a low potential for toxicity: the only remarkable toxic effect seen in rats after inhalation exposure to 1,1,1,3,3-pentafluoropropane in concentrations of up to 50,000 ppm for 90 days was an increased incidence of diffuse myocarditis. To elucidate the possible role of biotransformation in 1,1,1,3,3-pentafluoropropane-induced cardiotoxicity, the biotransformation of 1,1,1,3,3-pentafluoropropane was investigated in rats after inhalation exposure and in rat and human liver microsomes. Male and female rats were exposed by inhalation to 50 000, 10 000, and 2000 ppm 1,1,1,3,3-pentafluoropropane for 6 h, urine was collected for 72 h, and metabolites excreted were identified by 19F NMR spectroscopy and quantified by GC/MS. Trifluoroacetic acid and inorganic fluoride were identified as major urinary metabolites of 1,1,1,3,3-pentafluoropropane; 3,3,3-trifluoropropanoic acid and 1,1,1,3,3-pentafluoropropane-2-ol were minor metabolites. The extent of 1,1,1,3,3-pentafluoropropane biotransformation after inhalation was dependent on exposure concentrations. Neither 3,3,3-trifluoropropanoic acid nor 3,3,3-trifluoropyruvic acid were metabolized to trifluoroacetic acid in vitro or in rats. In rat and human liver microsomes, 1,1,1,3,3-pentafluoropropane was biotransformed by a cytochrome P450-dependent reaction to trifluoroacetic acid and 3,3,3-trifluoropropanoic acid. Rates of trifluoroacetic acid formation were 99.2 +/- 20.5 pmol (mg of protein)(-)(1) min(-)(1) and of 3,3,3-trifluoropropanoic acid formation were 17.5 +/- 4.0 pmol (mg of protein)(-)(1) min(-)(1) in liver microsomes from male rats. In human liver microsomes, rates of trifluoroacetic acid formation ranged from 0 to 11.6 pmol (mg of protein)(-)(1) min(-)(1), and rates of 3,3,3-trifluoropropanoic acid formation ranged from 0.7 to 7.6 pmol (mg of protein)(-)(1) min(-)(1). The results show that 1,1,1,3,3-pentafluoropropane is metabolized at low rates in vivo and in vitro. The toxic effects of 1,1,1,3,3-pentafluoropropane may be associated with the formation of the minor metabolite 3,3,3-trifluoropropanoic acid, which is highly toxic in rats.

The development of environmentally acceptable fluorocarbons

“……”

The development of environmentally acceptable fluorocarbons

“……”

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

“…111 Studies with 86 revealed a unique C−C bond cleavage reaction as a major metabolic outcome, and certain products formed along the proposed pathway may have the potential to subtend toxicity (Scheme 15). 112 Following inhalation by rats, 86 was oxidized at C-3 by P450 enzymes to afford 1,1,1,3,3-pentafluoro-1propanol (87), which was excreted in urine. Alternatively, 87 degraded by the elimination of HF to afford the acyl fluoride 88, which was readily hydrolyzed to 3,3,3-trifluoropropanoic acid (89), another urinary metabolite.…”

Unique fluoroalkyl substituents: is there life after CF 3 ?

“…91 For example, the 2,2,2-triuoroethyl moiety, which is oen found in approved drugs and agrochemicals, is usually metabolized by cytochrome P450 oxidases to form triuoroacetaldehyde, which ultimately converts to tri-uoroacetic acid. [92][93][94] Thus, despite their growing presence in drugs, the CF 3 -containing groups may be less desirable for agrochemicals, which is why other groups are urgently needed to suggest alternative molecular substitutions.…”

The development of environmentally acceptable fluorocarbons

“……”

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

“…111 Studies with 86 revealed a unique C−C bond cleavage reaction as a major metabolic outcome, and certain products formed along the proposed pathway may have the potential to subtend toxicity (Scheme 15). 112 Following inhalation by rats, 86 was oxidized at C-3 by P450 enzymes to afford 1,1,1,3,3-pentafluoro-1propanol (87), which was excreted in urine. Alternatively, 87 degraded by the elimination of HF to afford the acyl fluoride 88, which was readily hydrolyzed to 3,3,3-trifluoropropanoic acid (89), another urinary metabolite.…”

Unique fluoroalkyl substituents: is there life after CF 3 ?

“…91 For example, the 2,2,2-triuoroethyl moiety, which is oen found in approved drugs and agrochemicals, is usually metabolized by cytochrome P450 oxidases to form triuoroacetaldehyde, which ultimately converts to tri-uoroacetic acid. [92][93][94] Thus, despite their growing presence in drugs, the CF 3 -containing groups may be less desirable for agrochemicals, which is why other groups are urgently needed to suggest alternative molecular substitutions.…”

The development of environmentally acceptable fluorocarbons

“……”

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

“…111 Studies with 86 revealed a unique C−C bond cleavage reaction as a major metabolic outcome, and certain products formed along the proposed pathway may have the potential to subtend toxicity (Scheme 15). 112 Following inhalation by rats, 86 was oxidized at C-3 by P450 enzymes to afford 1,1,1,3,3-pentafluoro-1propanol (87), which was excreted in urine. Alternatively, 87 degraded by the elimination of HF to afford the acyl fluoride 88, which was readily hydrolyzed to 3,3,3-trifluoropropanoic acid (89), another urinary metabolite.…”

Unique fluoroalkyl substituents: is there life after CF 3 ?

“…91 For example, the 2,2,2-triuoroethyl moiety, which is oen found in approved drugs and agrochemicals, is usually metabolized by cytochrome P450 oxidases to form triuoroacetaldehyde, which ultimately converts to tri-uoroacetic acid. [92][93][94] Thus, despite their growing presence in drugs, the CF 3 -containing groups may be less desirable for agrochemicals, which is why other groups are urgently needed to suggest alternative molecular substitutions.…”