Methenamine

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: public available study ( non GLP, non guideline)

Objective of study:

absorption

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Public available literature. No guideline indicated. For details on method see materials and methods section.

GLP compliance:

not specified

Radiolabelling:

no

Species:

human

Sex:

male/female

Details on test animals or test system and environmental conditions:

Ten healthy volunteers participated in the study. Six of them were women (mean age 30 years, range 24-42, mean weight 57 kg, range 50-65) and four men (mean age 27 years, range 21-34; mean weight 67 kg, range 59-79).

Route of administration:

other: oral: tablets

Vehicle:

not specified

Details on exposure:

Subjects received methenamine hippurate via tablet.

Duration and frequency of treatment / exposure:

The study consisted of two eight-day periods between which there was an interval of a week. The subjects took in a cross-over design, one tablet at 8 a.m. on the first morning, and from the second morning onwards one tablet at 8 a.m. and 8 p.m. The last tablet was taken on the 7th day at 8 a.m.. On the 1st, 6th and 7th morning the tablet was taken on an empty stomach after night of fasting and eating was not permitted until 10 a.m., but the subjects drank 250 mL water at 7 a.m. and 200 mL at 8, 9, 10 and 12 a.m. There were no dietary restrictions on the other days.

Remarks:

Doses / Concentrations:
1000 mg methenamine hippurate per dose (see above).

No. of animals per sex per dose / concentration:

6 females and 4 males

Control animals:

no

Positive control reference chemical:

no positive control

Details on study design:

see above

Details on dosing and sampling:

On the 1st, 6th and 7th day blood samples were withdrawn 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h after ingestion of the tablet. Urine was collected on the 1st and 7th day in fractions of 0-2, 2-4, 4-6,6-12 and 12-24 h. On the 6th day the first fraction was omitted. The pH of the fractions was determined.
Methenamine itself was determined by gas chromatography from serum and urine samples.

Statistics:

Students t-test

Preliminary studies:

no preliminary study

Details on absorption:

The mean halflife in blood was reported as 4.3 h (range 2.8 - 6.0 h). The distribution volume was 0.56 l/kg.

Details on excretion:

On successive daily application approximately 90% of the dose was excreted in the urine during each 12 h dosing interval.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 4.3 h

Test no.:

#1

Toxicokinetic parameters:

AUC: 183 mg/L * h

Metabolites identified:

not specified

Details on metabolites:

not examined.

Conclusions:

no bioaccumulation potential based on study results
Methenamine is excreted very fast. No bioaccumulation is expected.

Executive summary:

In a well documented pharmacokinetic study, ten healthy volunteers, 6 women and 4 men, were given two formulations of methenamine hippurate as a single dose (1 g, about 450 mg base) on the first day and thereafter 1 g twice daily for 8 d, and - after a treatment-free period of one week - the second formulation was administered for another 8 d. After a single dose maximum serum concentration was achieved in about 1 h. The mean half life in blood was reported as 4.3 h. The distribution volume was 0.56 l/kg. On successive daily application approximately 90% of the dose was excreted in the urine during each 12 h dosing interval. Methenamine itself was determined by gas chromatography from serum and urine samples.

Description of key information

Methenamineis rapidly absorbed (90% of the dose within 12 h), distributed via the plasma and quickly (90% within 12 h) excreted mostly unchanged in the urine after oral uptake in man. Approximately 10 – 20 % of an oraldoesofmethenamineis converted to formaldehyde. The meanhalf lifein blood was reported as 4.3 h.Methenaminecan pass the placenta and is detectable in breast milk of lactatingwomen,however, no accumulation was seen. There are no data from studies following dermal administration or inhalation exposure ofmethenamine, but a similar behavior can be expected as soon as distribution via the plasma takes place. From the logKowof -2.18methenamineis expected to be systemically available after dermal exposure.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

90

Additional information

Toxicokinetics, metabolism and distribution

Absorption

Methenamine and its salts (e.g. methenamine mandelate or methenamine hippurate) are rapidly absorbed from the intestinal tract. After oral administration of a single dose of 1 g methenamine hippurate (about 450 mg base) to four volunteers (Allgen et al., 1979), maximal plasma levels of 70 – 100 μmol/l were reached within 1 to 2 h, the concentrations declined with a half-life of about 4 h. The average distribution volume was about 0.6 l/kg which is close to the total body water in adults. After multiple dosing of methenamine hippurate (1 g methenamine hippurate every 12 h over a total period of 3 d), about 80% of the dose administered each period was recovered in the urine within 12 h thereafter indicating that at least this amount has been absorbed. The methenamine determination in serum and urine was based on hydrolysis of the compound to formaldehyde in acid solution and subsequent colorimetric determination of formaldehyde, consequently any "free" formaldehyde present in the sample will also be determined(see also Gollamudi et al., 1981).

Distribution

Methenamine is quickly distributed via the plasma and excreted via the urine.

In a well documented pharmacokinetic study (Klinge et al., 1982), ten healthy volunteers, 6 women and 4 men, were given two formulations of methenamine hippurate as a single dose (1 g, about 450 mg base) on the first day and thereafter 1 g twice daily for 8 d, and - after a treatment-free period of one week - the second formulation was administered for another 8 d. After a single dose maximum serum concentration was achieved in about 1 h. The mean halflife in blood was reported as 4.3 h. The distribution volume was 0.56 l/kg. On successive daily application approximately 90% of the dose was excreted in the urine during each 12 h dosing interval. Methenamine itself was determined by gas chromatography from serum and urine samples.

Furthermore, methenamine can slowly pass the placenta, is detectable in the amniotic fluid and in breast milk. The methenamine concentrations in breast milk of lactating women was found to be in the same range as found in maternal plasma. Therefore the authors concluded that no accumulation of methenamine occurs in milk (Allgen et al., 1979).

Metabolism

From the distribution-excretion-balance, it can be assumed that approximately 10-20 % of an oral dose of methenamine is converted to formaldehyde and ammonia in the stomach (Gleckman et al., 1979). Gandelman administered methenamine mandelate to healthy men as oral doses of 1 g, 4 x daily. The pH of the inhibitory urine specimens ranged from 5.7 to 6.2. The average content of „free“ formaldehyde was about 6% in urine.

No data are available from detailed studies, but ingested formaldehyde, which is formed in amounts of about 10 – 20 % from an oral dose of methenamine, is rapidly taken up and metabolized as shown by the blood increase of formate in dogs (Restani et al., 1991). The time of transformation of formaldehyde into formic acid, its principal metabolite, is only 1 min in many animal species including man. The half-life of formic acid is 55 min (Restani et al., 1991).

It has been postulated that bis(chlormethyl)ether may be formed in the stomach from the reaction of formaldehyde with chloride ions (Hanselaar et al., 1983). This seems to occur easily when the chemical is in the gaseous phase but less so in liquid phases (Travenius,1982). The ether was not detectable in liquid phases (detection limit 10 ppb in aqueous solution and 1 ppb in gaseous medium respectively, Tuo et al., 1974).

Some studies examined the effect of the pH in the urine on the conversion rate of methenamine to formaldehyde in vitro and in vivo when used as medicinal antimicrobial agent (Gandelman, 1967; Gollamudi et al.,1981; Musher et al., 1974; Strom et al., 1993). In an acidic medium, the rate of hydrolysis of methenamine to formaldehyde and ammonia is dependent on pH. The hydrolysis occurs more rapidly at lower pH values (e.g. after oral administration to man in the stomach and the urine).

Musher et al. (1974) as well as Strom et al. (1993) studied the methenamine metabolism in vitro. Both groups have shown that in an acidic medium methenamine is hydrolyzed at a rate which is primarily dependent on pH. The dynamics of the urinary tract is also important, whereas the dosage form (base or salt) plays a minor role. Bactericidal concentrations of formaldehyde in urine (>28 µg/ml) were achieved within 3 h in urine at pH 6.0 and containing methenamine at 750 µg/ml. The half-life of methenamine conversion to formaldehyde increased approximately 20 times from 20 h at pH 5.0 to about 400 h at pH 6.5 (Strom et al., 1993).

Excretion

After multiple dosing of methenamine hippurate (1 g) for 3 d, about 80% of the dose administered each period was recovered in the urine within 12 h thereafter indicating that at least this amount has been absorbed. The methenamine determination in serum and urine was based on hydrolysis of the compound to formaldehyde in acidic solution and subsequent colorimetric determination of formaldehyde. It should be noted that this method for determination will include any "free" formaldehyde present in the sample (see also Gollamudi et al., 1981).

In a well documented pharmacokinetic study (Klinge et al., 1982), ten healthy volunteers, 6 women and 4 men, were given two formulations of methenamine hippurate as a single dose (1 g, about 450 mg base) on the first day and thereafter 1 g twice daily for 8 d, and - after a treatment-free period of one week - the second formulation was administered for another 8 d. On successive daily application approximately 90% of the dose was excreted in the urine during each 12 h dosing interval. Methenamine itself was determined by gas chromatography from serum and urine samples.

Gollamudi et al. (1981) determined the urinary excretion of both methenamine and formaldehyde for 48 hr after the oral administration of 10 different methenamine products (active ingredients were methenamine or its mandelate or hippurate) to ten human volunteers in a crossover study. There were no significant differences (p > 0.05) among methenamine and its various salts in terms the cumulative excretion of total methenamine (about 70 to 83 % of the dosis)or the total excretion of "free" formaldehyde (about 5.5 % of the doses).

Gollamudi et al. (1981) determined the urinary excretion of both methenamine and formaldehyde for 48 hr after the oral administration of 10 different methenamine products (active ingredients were methenamine or its mandelate or hippurate) to ten human volunteers in a crossover study. There were no significant differences (p > 0.05) among methenamine and its various salts in terms of the cumulative excretion of total methenamine (about 70 to 83% of the dosis) or the total excretion of "free" formaldehyde (about 5.5% of the dose).

Conclusions

Methenamine is rapidly absorbed (90% of the dose within 12 h), distributed via the plasma and quickly (90% within 12 h) excreted mostly unchanged in the urine after oral uptake in man. Approximately 10 – 20 % of an oral does of methenamine is converted to formaldehyde. The mean half life in blood was reported as 4.3 h. Methenamine can pass the placenta and is detectable in breast milk of lactating women, however, no accumulation was seen. There are no data from studies following dermal administration or inhalation exposure of methenamine, but a similar behavior can be expected as soon as distribution via the plasma takes place. From the log Kow of -2.18 methenamine is expected to be systemically available after dermal exposure.

References

Allgen, L.-G., Holmberg, G., Persson, B., Sörbo, B. (1979): Biological fate of methenamine in man. Acta Obstet. Gynecol. Scand.58, 287-293

Gandelman, A. (1967): Methenamine mandelate: Antimicrobial activity in urine and correlation with Formaldehyde levels. J. Urol. 97, 533-536

Gleckman, R., Alvarez, S., Joubert, D.W., Matthews, S.J. (1979): Drug therapy reviews: methenamine mandelate and methenamine hippurate. Am. J. Hosp. Pharm. 36, 1509-1512

Gollamudi, R., Straughn, A.B., Meyer, M.C. (1981): Urinary excretion of methenamine and formaldehyde: evaluation of 10 methenamine products in humans. J. Pharm. Sci. 70, 596-599

Hanselaar, A.G.J, Ariens, E.J., Henderson, P.T., Simonis, A.M. (1983): Methenamine - a Trojan horse? Deutsche Apotheker Zeitung 123, 862-863

Klinge, E., Männistö, P., Mäntylä, R., Lamminsivu, U., Ottoila, P. (1982): Pharmacokinetics of methenamine in healthy volunteers. J. Antimicrobial. Chemotherapy 9, 209-216

Musher, D.M., Griffith, D.P. (1974): Generation of formaldehyde from Methenamine: effect of pH and concentration, and antibacterial effect. Antimicrobial Agents and Chemotherapy 6, 708-711

Restani, P., Galli, C.L. (1991): Oral toxicity of formaldehyde and its derivates, CRC Crit. Rev. Toxicol. 21, 315-328

Strom, J. G., Jr., and H. Won Jun (1980): Journal of Pharmaceutical Sciences 69, 11, 1261 - 1263

Tou, J.C., Kallos, G.J. (1974): Study of aqueous HCl and formaldehyde mixtures for formation of bis(chloromethyl)ether. Am. Ind. Hyg. Assoc. J. 35, 419-422

Travenius, S.Z. (1982): Formation and occurrence of bis(chloromethyl)ether and its prevention in the chemical industry. Scand. J. Work Environ. Health 8, 1-86