Methenamine

Basic toxicokinetics

Administrative data

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)

Data source

Reference

Reference Type:

publication

Title:

Pharmacokinetics of methenamine in healthy volunteers.

Author:

Klinge, E., Männistö, P., Mäntylä, R., Lamminsivu, U., Ottoila, P.

Year:

1982

Bibliographic source:

J. Antimicrobial. Chemotherapy 9, 209-216

Materials and methods

Objective of study:

absorption

excretion

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Methenamine

EC Number:

202-905-8

EC Name:

Methenamine

Cas Number:

100-97-0

Molecular formula:

C6H12N4

IUPAC Name:

1,3,5,7-tetraazatricyclo[3.3.1.1³,⁷]decane

Test material form:

solid: crystalline

Radiolabelling:

no

Test animals

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).

Administration / exposure

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.

Doses / concentrations

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

Results and discussion

Preliminary studies:

no preliminary study

Toxicokinetic / pharmacokinetic studies

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.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 4.3 h

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

AUC: 183 mg/L * h

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

not examined.

Applicant's summary and conclusion

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.