Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Adequacy of study:
weight of evidence

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Bioavailability varied from about 9% in the monkey to 39% in the chimpanzee. The bioavailability values for dogs and rats were about 25% and 33%, respectively.
Type:
distribution
Results:
The volume of distribution at steady state (Vdss) of losartan and L 158641 was small. Small Vdss in multiple species suggests limited distribution to the tissues, perhaps because of strong plasma protein binding of the drugs
Type:
metabolism
Results:
With the exception of the carboxylic acid metabolite, L 158641, all metabolites showed much lower pharmacological activity than did the parent drug by in vitro angiotensin II receptor binding assay.
Type:
excretion
Results:
Following administration of an IV dose of 14C-losartan potassium to rats, 90% of the dose was excreted in the feces and 4.2% in the urine in 48 hours

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Hydroxylation of the butyl side chain of losartan to the monohydroxybutyl derivatives L 158795 (ω 1) and L 158796 (ω 3).

The maximal formation rates (Vmax) of L 158641 from losartan and L 158610 were estimated to be about 0.1 and 2 nmol/nmol P-450/minute, respectively, indicating that the conversion of losartan to its aldehyde intermediate (L 158610) is the rate-limiting step in the biotransformation of losartan to its active metabolite, L 158641.

In the rat, the primary route of metabolism was oxidative, leading to either monohydroxylated or other oxidized (e.g., L 158641) metabolites, whereas in monkeys, glucuronidation of the tetrazole moiety predominated. The metabolism of losartan by human liver slices, however, was not dominated by a single metabolic pathway, as with rats and monkeys, but was characterized by an approximately equal distribution of both oxidized and glucuronidated metabolites. When losartan was incubated with dog hepatocytes, the tetrazole-N2-glucuronide (L 158783) was the major metabolite. In addition to the glucuronide, 3 minor metabolites were identified in hepatocyte incubations: ω 1 hydroxylated, ω 3 hydroxylated, and the active carboxylic acid metabolite. With the exception of the carboxylic acid metabolite, L 158641, all metabolites showed much lower pharmacological activity than did the parent drug by in vitro angiotensin II receptor binding assay.

Bioaccessibility

Bioaccessibility testing results:
Bioavailability varied from about 9% in the monkey to 39% in the chimpanzee. The bioavailability values for dogs and rats were about 25% and 33%, respectively.

Applicant's summary and conclusion

Conclusions:
Data reported here are for studies with the read-across substances: Losartan Potassium and L-158641.