PHARMACOKINETICS PARAMETERS OF LISINOPRIL AND VALSARTAN A Molecular Pharmacology Midterm Presentation by Tin Ho
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…
ZZZ ???
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