The metabolism and pharmacokinetics of cyclohexylamine and their relevance to testicular toxicity

Roberts, Ashley (1987) The metabolism and pharmacokinetics of cyclohexylamine and their relevance to testicular toxicity. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Previous studies have shown that chronic administration of cyclohexylamine at dose levels greater than 200mg/kg/day result in testicular atrophy in rats but not mice. The species specificity could arise from differences in metabolism, pharmacokinetics or target organ sensitivity. The metabolism of [¹⁴C]cyclohexylamine showed a marked species difference over a wide range of doses. Male Wistar rats eliminated approximately 20% of the dose as 3- and 4-aminocyclohexanols, whilst male CD1 mice excreted negligible amounts of the hydroxylated metabolites. The DA strain of rat excreted low levels of aminocyclohexanols (5% of dose). This pattern of metabolism was confirmed throughout a combined metabolism and toxicity study in which Wistar and DA rats and mice were given a toxic dose of cyclohexylamine (400mg/kg/day given as the hydrochloride) for 13 weeks. The aminocyclohexanols were detected consistently in the plasma and testes of the Wistar rats but not in the mice of DA rats. The formation of these metabolites did not correlate with testicular effects since atrophy was found in both strains of rats, but not in mice. In vitro studies using the rat anococcygeus muscle showed that cyclohexylamine was about ten times more potent than the hydroxylated metabolites as an indirect sympathomimetic compound. Dose-dependent increases in the terminal half-life and time to peak concentration were found in male rats following a single oral dose of [¹⁴C]cyclohexylamine. This was associated with a decrease in plasma clearance. In vivo and in vitro studies indicated saturable active renal tubular secretion of cyclohexylamine in the rat. The plasma clearance in the mouse was about twice that in the rat and the pharmacokinetics did not show clear evidence of dose-dependency over the range studied. Chronic ad libitum administration of cyclohexylamine in the diet (0-0.9% cyclohexylamine given as the hydrochloride) was associated with a non-linear relationship between the concentration in plasma or testes and the daily intake in rats, but not in mice. The non-linearity in rats was apparent at doses greater than 200mg/kg/day, which corresponds to the steep increase in the dose response for testicular atrophy in this species. Intakes of approximately 750mg/kg/day were necessary in mice to produce plasma and testes concentrations of cyclohexylamine similar to those found in rats fed a clearly toxic dose (300mg/kg/day). Thus, inter-species and dose-dependent differences in pharmacokinetics may contribute to the species differences and dose response relationship for cyclohexylamine induced testicular toxicity.

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