PHARMACOKINETICS PARAMETERS OF LISINOPRIL AND VALSARTAN

A Molecular Pharmacology Midterm Presentation by Tin Ho

The Protagonists

Generic name(Trade name)

Lisinopril (Prinivil, Zestril)

Valsartan(Diovan)

Indications Hypertension,congestive heart failure, heart attacks.

Hypertension,congestive heart failure, post-myocardial infraction

Off-label N/A Alzheimer, Dementia

Class of drug Non-sulfhydryl ACE inhibitor

Angiotensin receptor blocker

Reason for selection Family member takes it “Work made me take it”

The Makers

Prinivil (Lisinopril) Diovan (Valsartan)Original Manufacturer Merck NovartisApproval date Dec 29, 1987 Dec 23, 1996 (capsule)

Jul 18, 2001 (tablet)Generic Manufacturer Sandoz, Ivax, Vintage… (Patent expires 2012)Generic approval date Jul 1, 2002 Oct 25, 2007 (tentative)Price – brand name $1.22/tablet $2.33/tabletPrice – generic Target $4/30days supply N/A

Basic Chemical Properties

Durg Lisinopril ValsartanMolecular Formula C21H31N3O5 C24H29N5O3

Molecular Weight 405.22 435.22Chemical Structure

3D Wire Models

Lisinopril

http://molinspiration.com/cgi-bin/galaxy?smiles=NCCCC%5BC%40H%5D(N%5BC%40%40H%5D(CCC1%3DCC%3DCC%3DC1)C(O)%3DO)C(%3DO)N1CCC%5BC%40H%5D1C(O)%3DO

Valsartan

http://molinspiration.com/cgi-bin/galaxy?smiles=CCCCC(%3DO)N(CC1%3DCC%3DC(C%3DC1)C1%3DC(C%3DCC%3DC1)C1%3DNNN%3DN1)%5BC%40%40H%5D(C(C)C)C(O)%3DO

Space Filler Models

Lisinopril

http://molinspiration.com/cgi-bin/galaxy?smiles=NCCCC%5BC%40H%5D(N%5BC%40%40H%5D(CCC1%3DCC%3DCC%3DC1)C(O)%3DO)C(%3DO)N1CCC%5BC%40H%5D1C(O)%3DO

Valsartan

http://molinspiration.com/cgi-bin/galaxy?smiles=CCCCC(%3DO)N(CC1%3DCC%3DC(C%3DC1)C1%3DC(C%3DCC%3DC1)C1%3DNNN%3DN1)%5BC%40%40H%5D(C(C)C)C(O)%3DO

The Obligatory Geeky StuffDrug Lisinopril ValsartanSMILES NCCCC[C@H](N[C@@H]

(CCC1=CC=CC=C1)C(O)=O)C(=O)N1CCC[C@H]1C(O)=O

CCCCC(=O)N(CC1=CC=C(C=C1)C1=C(C=CC=C1)C1=NNN=N1)[C@@H](C(C)C)C(O)=O

InChI InChI=1S/C21H31N3O5/c22-13-5-4-9-16(19(25)24-14-6-10-18(24)21(28)29)23-17(20(26)27)12-11-15-7-2-1-3-8-15/h1-3,7-8,16-18,23H,4-6,9-14,22H2,(H,26,27)(H,28,29)/t16-,17-,18-/m0/s1

InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1

Basic FactsDrug Lisinopril ValsartanLegal status Approved

Rx onlyApprovedRx only

Mode of administration Oral • tablet

Oral • tablet• hard gelatin capsule (discontinued in US)

Serum Therapeutic Concentration

20-70 μg/L 1.27-5.12 mg/L

Common dosage (mg/day)

5-40 80-160, max 320

Other info Less effective in Blacks than non-Black

Lipiniski Rule of 5Drug Lisinopril ValsartanlogP Octanol-Water Partition Coefficient

-0.9 5.8

Molecular Weight 405.4879 435.5188H-donor 5 2H-acceptor 8 8

Need some of this:

 

 

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Now the really exciting ADME stuff begins…

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Absorption ParametersDrug Lisinopril ValsartanpKa 3.85 8.15logP -0.9 5.8Solubility• Water• Methanol• Ethanol

• Soluble (13 mg/L)• Sparingly• Insoluble

• Soluble (23.4 mg/L)• Soluble• Soluble

Tmax 7 hrs 2-4 hrs

Cmax 49 ng/mL 2.208 ug/mL

Bioavailability 25% (range 6-60%)• 16% lower for patients

with Congestive Heart Failure (Class II-IV).

• Food does not affect absorption.

25% (range 10-35%)• Suspension provides 1.6x more

bioavailability compared to tablet.• Hepatic insufficiency may cause

exposure to 2x.• Food decrease exposure by 40%.

PK Plot – Lisinopril

http://www.cde-antibiotice.com/abi.client.en/bioanalytics/research.wtt.php?p_page=cmVzZWFyY2gtY28=&pp_page=YmlvYW5hbHl0aWNzLWNv&c_lang=ZW4=&c_page=TGlzaW5vcHJpbA==

Tmax 6.24 h

Cmax 49.83 ng/mL

T1/2 7.35 h

PK Plot – Valsartan

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097505/

Tmax 4.02 h

Cmax 2.208 ug/mL

T1/2 9.5 h

Distribution ParametersDrug Lisinopril ValsartanVd

• Cross placenta?• Cross brain/blood

barrier?

168L (2.4 ± 1.4 L/kg)YesPoorly

17L (0.23 ± 0.09 L/kg)--

Plasma protein binding None found 94-97%, primarily serum albumin

Bioaccumulation None found except in placenta, but not in fetus (mouse model)

-

FDA Biopharmaceutics Classification System

Class 3 Class 3

Metabolism ParametersDrug Lisinopril ValsartanHepatic metabolism None 80% unchanged.  

CYP2C9 produces 4-OH-valsartan, inactive.

Drug-Drug interaction None reported.Maybe taken w/ diuretic,Effects are typically additive.

Unlikely.

Drug-Food interaction Potassium level may increase, use caution w/ salt-substitute.Low Dietary Sodium increases effect of ACE inhibitor therapy.

No Potassium-based salt-substitute.

Excretion ParametersDrug Lisinopril ValsartanMode of excretion ~100% renal (unchanged).

Removed by hemodialysis.

Urine: 29% ± 5.8%Biliary: 70%Not removed by hemodialysis.

T1/2 (hours) 12Longer if • Aged• Renal Disease

9.4 ± 3.8Longer if • Aged

Clearance(mL/min/kg)

4.2 ± 2.2

Reduced for • Aged • Congestive Heart

Failure• Renal Disease

0.49 ± 0.091.07 (patients with heart failure)Reduced for • Aged• Liver diseaseMonitor if• Renal Disease

Kinetics order First order First order

Summary• PD presentation for final would learn more about the

drugs…• Listen to your doctor!• Digitization of health-related business is going to change

the industry dramatically in the next 10-15 years.

Sources• Wikipedia• PDB.net• RxList.com• Drugs.com• DrugBank.ca• ChemSpier.com• ChemAxon (Chemicalize.org)• FDA AccessData• NCBI PubMed• molinspiration.com• cde-antibiotice.com• Analysis of Drugs and Poisons (mtnviewfarm.net)• Goodman and Gilman’s The Pharmacological Basis of

Therapeutics, 12th Ed.

Thank You!

I am riding 545 miles for a fundraiser.  Please consider a donation to the SF AIDS foundation: http://www.toFightHIV.org/goto/tinNo donation is too small! -Tin Ho

BACKUP SLIDES

Lisinopril IV vs PO

The pharmacokinetics of lisinopril in hospitalized patients with congestive heart failure by TILL et al

LisinoprilPK Params

Valsartan PK Parameters

Valsartan Elimination Kinetics

Stability, Degradation Kinetics and in vitro Bioequivalence Studies of Valsartan Tablets by Siddiqui et al

Sou

rces

with

link

sDrug Lisinopril Valsartan

wikipediahttp://en.wikipedia.org/wiki/Lisinopril

http://en.wikipedia.org/wiki/Valsartan

rxlisthttp://www.rxlist.com/prinivil-drug.htm    

http://www.rxlist.com/diovan-drug/clinical-pharmacology.htm

pdbnethttp://www.pdr.net/drugpages/concisemonograph.aspx?concise=839 fdaPrinivil:

fda links don't work!

Lisinopril: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=lisinopril

Lisinopril (Sandoz): http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?

fuseaction=Search.DrugDetails  ??

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=DIOVAN 

label Prinivil:http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019558s054lbl.pdf 

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021283s036lbl.pdf