1H-Imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Adequacy of study:

weight of evidence

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Losartan

IUPAC Name:

Losartan

Results and discussion

Main ADME results

Main ADME results 1

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.

Main ADME results 2

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

Main ADME results 3

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.

Main ADME results 4

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 (or Bioavailability)

Bioaccessibility (or Bioavailability) 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.