Toxicokinetic Characterization of Hexamethylenetetramine

Toxics. 2023 Mar 31; 11 (4): 337.

Authors: Kim W, Kim E, Lee J, Song CH, Jung W, Shin S, Kim KB, Shin BS, Kim TH.

Hexamethylenetetramine, an aldehyde-releasing agent, is used as a preservative in various food, cosmetics, and medical treatments, such as a treatment for urinary tract infections. It has been reported to be allergenic in contact with the skin, with the additional possibility of causing toxicity once absorbed systemically. Despite its potential toxicity, there are no reports on the in vivo bioavailability of hexamethylenetetramine following oral or dermal administration.

• Animals. Male Sprague-Dawley rats (7-8 weeks old, body weight 225-250 g) were kept in plastic cages with free access to a standard diet. For serial blood sampling, rats were anesthetized by intra-peritoneal injection, and polyethylene (PE) tubing was intubated into the jugular vein.
• IV Injection Study. Hexamethylenetetramine was dissolved in saline for iv injection at doses of 0.2 and 0.5 mg/kg. Blood samples (0.2 mL each) were collected via jugular vein at 0, 2, 5, 10, 15, and 30 min, and 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after injection.
• Oral Administration Study. Hexamethylenetetramine was dissolved in saline for iv injection at doses of 0.2 and 0.5 mg/kg. After overnight fasting, a dosing solution was injected via the penile vein. The injected dosing volume was constantly 1 mL/kg regardless of the dose. Blood samples (0.2 mL each) were collected via jugular vein at 0, 2, 5, 10, 15, and 30 min, and 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after injection.
• Percutaneous Absorption Study. For the percutaneous absorption study, gel formulation consisting of hexamethylenetetramine (0.15 or 0.6%), carbomer 940 (1.1%), and distilled water (98.75 or 98.3%) was used. After overnight fasting, 5 mg/cm² of hexamethylenetetramine gel was evenly applied to 4.5×4.5 cm² of the shaved area. Blood samples (0.2 mL each) were collected via jugular vein at 0, 5, 15, and 30 min, and 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 h after dosing.
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• Average plasma concentration-time profiles of hexamethylenetetramine obtained after iv injection, oral administration, and percutaneous administration are shown in the following figure.

Fig. 1 Average plasma concentration-time profiles of hexamethylenetetramine obtained after (a) iv injection, (b) oral, and (c) percutaneous administration in rats.

• After iv injection of 0.2 and 0.4 mg/kg of hexamethylenetetramine, a mono-exponential decline was observed in the plasma concentrations. Following oral administration, hexamethylenetetramine was quantifiable in the first plasma samples (5 min) and reached C_max at about 0.5 h. In the percutaneously administered group, hexamethylenetetramine was relatively slowly absorbed. The C_max was reached approximately 3 h after dosing.
• Following iv injection, t_1/2 was estimated as 1.26-1.36 h, and plasma concentration was below that of the LLOQ (BLOQ) at 8 h. For the oral administration, the t_1/2 was estimated as 1.12 h, and absolute bioavailability was calculated as 89.83%. Following percutaneous administration, t_1/2 was estimated as 1.69-2.43 h.

Most of the orally and percutaneously administered hexamethylenetetramine was absorbed into the systemic circulation. Following iv injection, the plasma concentration of hexamethylenetetramine showed mono-exponential decay, with an elimination half-life of about 1.3 h. Following oral administration, the T_max reached an average of 0.47 h, and bioavailability was estimated at 89.93%. After percutaneous administration, it reached C_max on average at 2.9-3.6 h.

In Vivo Toxicity Study

Bioanalytical Package

Administration Routes and Biofluid Sampling

Reference

1. Kim W, et al. (2023). "Development of an LC-MS/MS Assay and Toxicokinetic Characterization of Hexamethylenetetramine in Rats." Toxics. 11 (4), 337.

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