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

Endpoint summary

Description of key information

No data were identified for Losartan Free Acid.  The following data are for the read across substances Losartan potassium and L-158641.  The pharmacokinetic studies of losartan potassium and L-158641 in laboratory animals (rats, dogs, monkeys, and chimpanzees) are summarized briefly in this section.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No data were identified for Losartan Free Acid. The following data are for the read across substances Losartan Potassium (or Losartan) and L-158641 (the pharmacologically active metabolite of Losartan Potassium).

a.  Pharmacokinetics and Absorption

1)   Losartan Potassium

Following IV administration, plasma concentrations of losartan potassium declined in a multiexponential fashion in all species studied. The elimination kinetics was species-dependent. The plasma clearance (CL) was 22.2 mL/min/kg for the dog, 11.6 mL/min/kg for the monkey, 11.3 mL/min/kg for the chimpanzee, and 7 mL/min/kg for the rat; the respective terminal half-lives (t½) were 41, 51.6, 61.2 and 106 minutes. Absorption of losartan potassium was also species-dependent. 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.

2)   L‑158641

The absorption and elimination kinetics of L‑158641 were evaluated in rats and chimps. The elimination rate of L‑158641 from the body was much slower than that of the parent drug. The CL and terminal t½ were 2.12 mL/min/kg and 327 minutes in the rat, and 1.29 mL/min/kg and 402 minutes in the chimpanzee. When L‑158641 was given orally, bioavailability was about 12% in the rat and 35.4% in the chimpanzee. No losartan potassium was detected in plasma or urine in chimpanzees dosed with L‑158641.

b.  Sex-Dependent Kinetics

Gender differences in the elimination kinetics of losartan potassium were observed in rats when the drug was given intravenously. Male rats cleared the drug more rapidly than female rats. Unlike the rat, there were no gender-related differences in the plasma profiles of losartan potassium in the dog following chronic oral doses at 125 mg/kg/day.

c.  Formation of L‑158641

The fraction (fm) of losartan converted to its pharmacologically active metabolite, L‑158641, was calculated by comparing the AUCs of L‑158641 after IV administration of losartan potassium and IV administration of L‑158641. The fm was 29% in the rat and 5.5% in the chimpanzee.

d.  Distribution

The volume of distribution at steady state (Vdss) of losartan potassium and L‑158641 was small. The Vdss of losartan potassium varied from 0.16 L/kg in the monkey to 0.75 L/kg in the rat; Vdss of L‑158641 ranged from 0.27 L/kg in the chimpanzee to 0.45 L/kg in the rat. Small Vdss in these species suggests limited distribution to the tissues, perhaps because of strong plasma protein binding of the drugs (shown below).

1)   Plasma Protein Binding

Both losartan and L‑158641 were extensively bound to plasma protein [ECP‑39]. The unbound fractions of losartan were 0.8%, 1.3%, and 2.7% for rat, human, and dog plasma, respectively. Binding of L‑158641 to plasma protein was higher than that of losartan, and the unbound fraction for rat and human plasma was only 0.2%. Binding of the 2 drugs was concentration-independent over a wide concentration range (0.1 to 10 ug/mL), and over the pH range of 6.95 to 8.58. Studies with purified rat or human serum albumin, alpha1‑acid glycoprotein and gamma-globulins revealed that serum albumin is the major component of plasma protein responsible for the binding of losartan and L‑158641.

2)   Blood to Plasma Concentration Distribution Ratio [ECP-40]

Both losartan and L‑158641 were distributed primarily in the plasma component of human whole blood. The blood to plasma concentration distribution ratio values were 0.53 and 0.58 for losartan potassium and L‑158641, respectively. The ratios were independent of concentrations from 20 to 800 ng/mL.

3)   Tissue Distribution

Radioactivity (parent drug + metabolites) was widely distributed throughout the body after an IV dose of14C‑losartan potassium in rats. With the exception of liver and kidney, the levels of radioactivity in tissues were far less than those in plasma at all time points studied. Liver had the highest level of radioactivity, ~20 times that of plasma, and accounted for 40 to 60% of the administered dose at 0.25 and 1 hour after dosing. Radioactivity in all tissues declined with time, and there were only trace amounts of radioactivity in tissues 48 hours after IV administration. When14C‑losartan potassium was given orally to rats, widespread distribution of radioactivity was also observed, with the highest level in the liver.

4)   Placental Transfer

Following oral administration of14C-losartan to 18-day pregnant rats, the transfer of radioactivity across the placenta and its distribution into and removal from fetal tissues were very slow. Radioactivity in maternal tissues reached its peak within 1 hour after dosing, and declined with time, whereas radioactivity in fetal tissues increased gradually and reached its peak between 1 and 8 hours. The radioactivity in fetal tissues remained virtually unchanged from 8 to 24 hours. At 8 or 24 hours after dosing, radioactivity in the fetus accounted for 0.01% of the administered dose.

5)   Milk Transfer

Following oral administration of14C-losartan potassium to lactating rats, the radioactivity appeared in the milk as early as 30 minutes (the first time point) after dosing and reached the peak at 8 hours, indicating a slow milk transfer of the radioactivity. The radioactivity in the milk declined from 8 to 48 hours in parallel to that in plasma. The ratios of radioactive equivalents in milk to those in plasma increased with time. The ratio was 0.024 at 30 minutes; at 48 hours after dosing, the ratio was 0.45.

e.  Metabolism

1)   In Vitro Metabolism

The in vitro metabolism of losartan has been investigated extensively with liver slice preparations from rats, monkeys, and humans. The in vitro metabolism was different among the species. 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 potassium 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 vitroangiotensin II receptor binding assay. 

2)   Conversion of Losartan to L-158641

Evidence that losartan potassium is converted to its pharmacologically active metabolite, L‑158641, via the aldehyde intermediate, L‑158610 (E‑3179), was obtained by incubation with human liver microsomes. In an atmosphere of18O2, it was shown that losartan and L‑158610 were converted to L‑158641 in a reaction that was both NADPH- and oxygen-dependent, and that18O2 was incorporated into L‑158641. 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 vitro studies with specific enzyme inhibitors and recombinant isoforms of human cytochrome P-450 indicate that the conversion of losartan to L‑158641 is catalyzed by cytochrome P-450, and that both CYP2C and CYP3A isoforms are involved in this biotransformation.

3)   Conversion of Losartan to L‑158795 and L-158796[10]

In vitro studies with specific enzyme inhibitors indicate that both CYP2C and CYP3A isoforms are also involved in the hydroxylation of the butyl side chain of losartan to the monohydroxybutyl derivatives L‑158795 (ω‑1) and L‑158796 (ω‑3).

f.   Excretion

1)   Biliary Excretion

Following administration of an IV dose of14C-losartan potassium to rats, 90% of the dose was excreted in the feces and 4.2% in the urine in 48 hours. When14C‑losartan potassium was given to bile duct-cannulated rats, 95.5% of the dose was excreted in the bile in 48 hours (14.6% as unchanged parent drug, 26.6% as L‑158641 and 7.8% as the tetrazole-N2-glucuronide, L‑158783), with only4.2% in the urine and 0.7% in the feces, indicating that biliary excretion was the major route of elimination of radioactivity (parent drug + metabolites). Thus, losartan potassium undergoes extensive metabolism in the rat, while biliary excretion of unchanged drug contributes less to its overall elimination.

When14C‑losartan potassium was given intravenously to dogs, 72% of the dose was excreted in the feces and 19% in the urine in 168 hours, suggesting that the major route of radioactivity elimination was via the bile.

2)   Renal Excretion

In chimpanzees, renal clearance of losartan was 86.6 mL/min, which accounted for 14% of CL (619.2 mL/min). On the other hand, renal clearance of L‑158641 contributed significantly to its elimination. Following an IV dose of L‑158641, renal clearance was 40 mL/min, which accounted for ~55% of CL.