Valsartan

Valsartan is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination valsartan/hydrochlorothiazide, valsartan/amlodipine, valsartan/amlodipine/hydrochlorothiazide, or valsartan/sacubitril.

Valsartan was patented in 1990 and came into medical use in 1996. It is available as a generic medication. In 2020, it was the 123rd most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Structure:

Physicochemical Data:

IUPAC Name     (S)-3-methyl-2-(N-{[2′-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid
CAS Number137862-53-4
Molecular FormulaC24H29N5O3
Molecular Mass435.528 g·mol−1
Melting Point116-117°C
Density 

Pharmacokinetic Data:

AbsorptionAfter one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing doses over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration.
Volume of DistributionThe steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively.
Protein BindingValsartan is highly bound to serum proteins (95%), mainly serum albumin.
MetabolismValsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of the dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450-mediated drug interaction between valsartan and coadministered drugs is unlikely because of the low extent of metabolism.
Route of EliminationValsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of the dose) and urine (about 13% of the dose). The recovery is mainly an unchanged drug, with only about 20% of the dose recovered as metabolites.
Half-lifeAfter intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours.
ClearanceFollowing intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance).
ToxicityApproximate LD50 >2000 mg/kg (Gavage, rat)

References:

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