ctive metabolite is about 34 liters and 12 liters, respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Metabolism
Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 14% of an orally-administered dose of losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.
Elimination
Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6 to 9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.
Special Populations
Pediatric
Pharmacokinetic parameters after multiple doses of losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4 below. Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic parameters in adults and children are shown in the table below.
Table 2Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6 to 16 Following Multiple Dosing * Mean ± standard deviation
† Harmonic mean and standard deviation
‡ Median
Adults given 50 mg once daily for 7 days
N=12
Age 6 to 16 given 0.7 mg/kg once daily for 7 days
N=25
Parent
Active Metabolite
Parent
Active Metabolite
AUC0-24 (ng•hr/mL)*
442 ± 173
1685 ± 452
368 ± 169
1866 ± 1076
CMAX (ng/mL)*
224 ± 82
212 ± 73
141 ± 88
222 ± 127
T1/2 (h)†
2.1 ± 0.70
7.4 ± 2.4
2.3 ± 0.8
5.6 ± 1.2
TPEAK (h)‡
0.9
3.5
2.0
4.1
CLREN (mL/min)*
56 ± 23
20 ± 3
53 ± 33
17 ± 8
The bioavailability of the suspension formulation was compared with losartan tablet |
