Identification

Name
Piperaquine
Accession Number
DB13941
Type
Small Molecule
Groups
Approved, Investigational
Description

Piperaquine is an antimalarial agent first synthesized in the 1960's and used throughout China [1]. Its use declined in the 1980's as piperaquine resistant strains of Plasmodium falciparum appeared and artemisinin derivatives became available. It has come back into use in combination with the artemisinin derivative Artenimol as part of the combination product Eurartesim [Label]. Eurartesim was first authorized for market by the European Medicines Agency in October 2011.

Structure
Thumb
Synonyms
  • 1,3-bis[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propane
Product Ingredients
IngredientUNIICASInChI Key
Piperaquine tetraphosphateIHB5WLO51Q911061-10-4OAKKJVUSSVZQRF-UHFFFAOYSA-N
Categories
UNII
A0HV2Q956Y
CAS number
4085-31-8
Weight
Average: 535.52
Monoisotopic: 534.2065505
Chemical Formula
C29H32Cl2N6
InChI Key
UCRHFBCYFMIWHC-UHFFFAOYSA-N
InChI
InChI=1S/C29H32Cl2N6/c30-22-2-4-24-26(20-22)32-8-6-28(24)36-16-12-34(13-17-36)10-1-11-35-14-18-37(19-15-35)29-7-9-33-27-21-23(31)3-5-25(27)29/h2-9,20-21H,1,10-19H2
IUPAC Name
7-chloro-4-(4-{3-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propyl}piperazin-1-yl)quinoline
SMILES
ClC1=CC2=C(C=C1)C(=CC=N2)N1CCN(CCCN2CCN(CC2)C2=CC=NC3=C2C=CC(Cl)=C3)CC1

Pharmacology

Indication

For the treatment of uncomplicated Plasmodium falciparum infection in adults, children, and infants aged 6 months and up weighing over 5 kg [Label]. Used in combination with Artenimol.

Pharmacodynamics

Piperaquine inhibits the P. Falciparum parasite's haem detoxification pathway [4].

Mechanism of action

The mechanism of piperaquine inhibition of the haem detoxification pathway is unknown but is expected to be similar to that of Chloroquine.

Absorption

Piperaquine is slowly absorbed and exhibits multiple peaks in its plasma concentration curve suggestive of enterohepatic recycling occurring alongside the absorption process [4]. Due to this complication there is no discreet value for bioavailability but piperaquine is highly absorbed into systemic circulation. When taken with food, Cmax increases by 217% and mean exposure increases by 177%. Tmax is not affected by food and remains around 5 h [Label]. Piperaquine has been observed to accumulate more in females to a degree of 30-50% more than males [Label]. It also collects in red blood cells similar to Artenimol.

Volume of distribution

Piperaquine is thought to distribute into a central compartment with an apparent volume of 26.7 L/kg, and two peripheral compartments with apparent volumes of 76.8 L/kg and 617 L/kg [4]. These combine for a total volume of distribution of 720.5 L/kg.

Protein binding

Piperaquine's binding to plasma proteins is considered to be virtually complete [4]. It has been measured to be >99% in humans, rats, and dogs.

Metabolism

Piperaquine undergoes N-dealkylation, separating its aliphatic bridge from one of the nitrogen-containing rings [3]. The resulting aldehyde is then oxidized to a carboxylic acid to form metabolite 1 (M1). The same nitrogen-containing rings can also undergo hydroxylation at one of two sites to form M3 or M4. M2 is formed via N-oxidation of one of the nitrogens in the quinoline groups at either side of the molecule. M5 results when both of these nitrogens are oxidized. M1 and M2 are the major metabolism products [Label]. Each of these metabolites were observed in the urine.

Route of elimination

Piperaquine is mainly excreted in the feces with a negligible amount in the urine [Label].

Half life

The terminal elimination half-life was observed to be 576h or 24 days [4]. This is thought to be due to the extensive distribution of piperaquine.

Clearance

The mean apparent total clearance has been observed to be 1.12 L/h/kg in adult malaria patients [4].

Toxicity

Studies of piperaquine in monkeys and dogs have shown some hepatotoxicity and reversible depression in white blood cells and neutrophils [Label]. Additional observations include infiltration of macrophages with intracytoplasmic basophilic granular material consistent with phospholipidosis and degenerative lesions in numerous organs and tissues. These effects were seen at exposure levels similar to clinical dosing in humans. At high doses, piperaquine can interfere with cardiac conduction and produce effects on blood pressure. Mild phototoxicity has been observed with piperaquine in rats exposed to UV light.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe metabolism of Piperaquine can be decreased when combined with Abiraterone.
AcepromazineThe serum concentration of Acepromazine can be increased when it is combined with Piperaquine.
AceprometazineThe serum concentration of Aceprometazine can be increased when it is combined with Piperaquine.
Acetyl sulfisoxazoleThe metabolism of Piperaquine can be decreased when combined with Acetyl sulfisoxazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Piperaquine.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Piperaquine.
AlimemazineThe risk or severity of QTc prolongation can be increased when Piperaquine is combined with Alimemazine.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Piperaquine.
AmiodaroneThe metabolism of Piperaquine can be decreased when combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Piperaquine.
Food Interactions
Not Available

References

General References
  1. Davis TM, Hung TY, Sim IK, Karunajeewa HA, Ilett KF: Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65(1):75-87. [PubMed:15610051]
  2. Hoglund RM, Workman L, Edstein MD, Thanh NX, Quang NN, Zongo I, Ouedraogo JB, Borrmann S, Mwai L, Nsanzabana C, Price RN, Dahal P, Sambol NC, Parikh S, Nosten F, Ashley EA, Phyo AP, Lwin KM, McGready R, Day NP, Guerin PJ, White NJ, Barnes KI, Tarning J: Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. PLoS Med. 2017 Jan 10;14(1):e1002212. doi: 10.1371/journal.pmed.1002212. eCollection 2017 Jan. [PubMed:28072872]
  3. Tarning J, Bergqvist Y, Day NP, Bergquist J, Arvidsson B, White NJ, Ashton M, Lindegardh N: Characterization of human urinary metabolites of the antimalarial piperaquine. Drug Metab Dispos. 2006 Dec;34(12):2011-9. doi: 10.1124/dmd.106.011494. Epub 2006 Sep 6. [PubMed:16956956]
  4. EMA: Eurartesim Assessment Report [Link]
External Links
ChemSpider
109031
ChEBI
91231
ChEMBL
CHEMBL303933
PharmGKB
PA166104279
Wikipedia
Piperaquine
ATC Codes
P01BF05 — Artenimol and piperaquine
FDA label
Download (904 KB)
MSDS
Download (107 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1, 2CompletedOtherPlasmodium Infections1
3CompletedPreventionHealthy Volunteers1
4Not Yet RecruitingPreventionAnemias / Malaria caused by Plasmodium falciparum1
Not AvailableNot Yet RecruitingOtherControlled Human Malaria Infection / Gametocytes / Malaria caused by Plasmodium falciparum / Transmission1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0167 mg/mLALOGPS
logP5.53ALOGPS
logP5.27ChemAxon
logS-4.5ALOGPS
pKa (Strongest Basic)8.47ChemAxon
Physiological Charge3ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area38.74 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity153.42 m3·mol-1ChemAxon
Polarizability59.56 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Drug is a moderately sensitive substrate for CYP3A4 (change in AUC >2 fold with enzyme inhibitor).
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. EMA: Eurartesim Assessment Report [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Hanboonkunupakarn B, Ashley EA, Jittamala P, Tarning J, Pukrittayakamee S, Hanpithakpong W, Chotsiri P, Wattanakul T, Panapipat S, Lee SJ, Day NP, White NJ: Open-label crossover study of primaquine and dihydroartemisinin-piperaquine pharmacokinetics in healthy adult thai subjects. Antimicrob Agents Chemother. 2014 Dec;58(12):7340-6. doi: 10.1128/AAC.03704-14. Epub 2014 Sep 29. [PubMed:25267661]
  2. EMA: Eurartesim Assessment Report [Link]
  3. Eurartesim EMA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. EMA: Eurartesim Assessment Report [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. EMA: Eurartesim Assessment Report [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. EMA: Eurartesim Assessment Report [Link]

Drug created on January 04, 2018 14:59 / Updated on September 15, 2018 18:24