Identification

Name
Saquinavir
Accession Number
DB01232
Description

Saquinavir is an HIV-1 protease inhibitor used in combination with ritonavir and other antiretrovirals for the treatment of human immunodeficiency virus-1 (HIV-1) infection. In 1995 it became the first protease inhibitor approved by the FDA, followed shortly by ritonavir in 1996, and remains in clinical use today due to a relatively benign adverse effect profile as compared to other antiretroviral therapies.2 While its efficacy was initially limited by exceptionally poor oral bioavailability (approximately 4%),6 its current indications require the co-administration of ritonavir - a potent enzyme inhibitor - that increases the bioavailability and subsequent serum concentrations of saquinavir, thus dramatically improving antiviral activity.2,6,7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 670.8408
Monoisotopic: 670.38426874
Chemical Formula
C38H50N6O5
Synonyms
  • Saquinavir
External IDs
  • Ro 31 8959
  • Ro 31-8959
  • RO 31-8959/000
  • Ro 318959
  • RO-31-8959/000
  • Sch 52852
  • SCH-52852

Pharmacology

Indication

Saquinavir is indicated, in combination with ritonavir and other antiretroviral agents, for the treatment of HIV-1 infection in patients 16 years of age and older.6

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Saquinavir exerts its antiviral activity by inhibiting an enzyme critical for the HIV-1 viral lifecycle.6 Like other protease inhibitors, saquinavir has a propensity for participating in drug interactions - use caution when administering saquinavir to patients maintained on other pharmaceutical agents as pharmacodynamic and pharmacokinetic interactions are common.6 Saquinavir is known to increase the QTc-interval in otherwise healthy individuals, and should therefore be used with caution in patients maintained on other QTc-prolonging medications or for whom prolongation of the QTc-interval may be of particular consequence (e.g. patients with pre-existing heart disease).6 Careful and regular monitoring of patient bloodwork is recommended, as saquinavir has been associated with the development of metabolic complications (e.g. diabetes mellitus, hyperlipidemia) and worsening of pre-existing liver disease.6

Mechanism of action

The HIV lifecycle is comprised of 3 distinct stages: assembly, involving creation and packaging of essential viral components; budding, wherein the viral particle crosses the host cell plasma membrane and forms a lipid envelope; and maturation, wherein the viral particle alters its structure and becomes infectious.4 At the center of this lifecycle is the Gag polyprotein which, along with the products of its proteolysis, coordinate these stages and function as the major structural proteins of the virus. The HIV-1 protease enzyme, a dimeric aspartic protease, is the enzyme responsible for cleaving the Gag polyprotein and thus plays a critical role in many aspects of the HIV viral lifecycle.4

Saquinavir is an inhibitor of the HIV-1 protease enzyme.6 Its design is based on the "peptidomimetic" principle, wherein the molecule contains a hydroxyethylene scaffold that mimics the normal peptide linkage (cleaved by HIV protease) but which itself cannot be cleaved.5 By preventing HIV-1 protease activity, and thus the proteolysis of the Gag polyprotein, saquinavir results in the production of immature, non-infectious viral particles.

TargetActionsOrganism
AHuman immunodeficiency virus type 1 protease
inhibitor
Human immunodeficiency virus 1
Absorption

The absolute bioavailability of orally administered saquinavir is only ~4%,6 thought to be a consequence of incomplete absorption and extensive first-pass metabolism. It is co-administered with ritonavir, another protease inhibitor and a potent inhibitor of the enzymes responsible for saquinavir's first-pass metabolism, in order to dramatically boost its serum concentrations and, by extension, its therapeutic efficacy. Following administration of saquinavir 1000mg twice daily with ritonavir 100mg twice daily the AUC24h at steady-state was 39026 ng.h/mL.6

Volume of distribution

The steady-state volume of distribution of saquinavir is approximately 700 L, suggesting extensive distribution into tissues.6

Protein binding

Saquinavir is approximately 98% plasma protein-bound independent of serum concentration.6

Metabolism

Saquinavir is extensively metabolized in the liver following oral administration, and in vitro studies have shown that >90% of its biotransformation is mediated by the CYP3A4 isoenzyme. Saquinavir is rapidly metabolized to a number of inactive mono- and di-hydroxylated compounds.6

Hover over products below to view reaction partners

Route of elimination

The primary means of elimination of saquinavir appears to be extensive hepatic metabolism followed by fecal excretion of both the parent drug and metabolic products.6 Following the administration of radiolabeled saquinavir (both orally and intravenously), approximately 81-88% of radioactivity is recovered in the feces within 5 days of dosing while only 1-3% is recovered in the urine. Mass balance studies indicate that only 13% of orally-administered plasma radioactivity is attributed to unchanged parent drug, with the remainder comprising metabolic products of saquinavir's hepatic metabolism. In contrast, intravenous administration resulted in approximately 66% of the circulating plasma radioactivity being attributed to unchanged parent drug, suggesting a high degree of first-pass metabolism with oral administration.6

Half-life
Not Available
Clearance

The systemic clearance of saquinavir is approximately 1.14 L/h/kg following intravenous administration.6

Adverse Effects
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Toxicity

The oral LD50 of saquinavir in both rats and mice is >5 g/kg.8 Data regarding overdose with saquinavir are limited.6 No acute toxicities or sequelae were noted in a patient ingesting 8 grams of saquinavir as a single dose, and a second subject ingesting 2.4 grams as a single dose experienced throat pain that lasted for 6 hours and subsequently resolved.6 Treatment of overdose should consist of symptomatic and supportive measures. Dialysis is unlikely to be of benefit given saquinavir's extensive protein-binding.6

Affected organisms
  • Human Immunodeficiency Virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Saquinavir can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Saquinavir can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Saquinavir can be decreased when combined with Abemaciclib.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Saquinavir.
AcalabrutinibThe metabolism of Saquinavir can be decreased when combined with Acalabrutinib.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Saquinavir.
AcebutololThe risk or severity of QTc prolongation can be increased when Saquinavir is combined with Acebutolol.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Saquinavir.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Saquinavir.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Saquinavir.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid grapefruit products. Co-administration with grapefruit-containing products inhibits the metabolism of saquinavir.
  • Take after a meal.

Products

Product Ingredients
IngredientUNIICASInChI Key
Saquinavir mesylateUHB9Z3841A149845-06-7IRHXGOXEBNJUSN-YOXDLBRISA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FortovaseCapsule, liquid filled200 mg/1OralGenentech, Inc.1997-11-072012-04-18US flag
Fortovase RocheCapsuleOralHoffmann La Roche1998-11-262007-03-06Canada flag
InviraseTablet, film coated500 mgOralRoche Registration Gmb H1996-10-04Not applicableEU flag
InviraseTablet, film coated500 mg/1OralState of Florida DOH Central Pharmacy2009-07-01Not applicableUS flag
InviraseTablet500 mgOralHoffmann La Roche2006-04-10Not applicableCanada flag
InviraseCapsule200 mg/1OralGenentech, Inc.1995-12-06Not applicableUS flag
InviraseCapsule200 mgOralRoche Registration Gmb H1996-10-04Not applicableEU flag
InviraseCapsule200 mg/1OralREMEDYREPACK INC.2013-05-012013-05-02US flag
InviraseTablet, film coated500 mg/1OralGenentech, Inc.2004-12-17Not applicableUS flag
Invirase - Cap 200mgCapsuleOralHoffmann La Roche1996-12-312018-12-31Canada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
J05AE01 — Saquinavir
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as quinoline carboxamides. These are quinolines in which the quinoline ring system is substituted by one or more carboxamide groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Quinoline carboxamides
Direct Parent
Quinoline carboxamides
Alternative Parents
Phenylbutylamines / Amphetamines and derivatives / Pyridinecarboxylic acids and derivatives / Piperidinecarboxamides / 2-heteroaryl carboxamides / Aralkylamines / Heteroaromatic compounds / Trialkylamines / Secondary carboxylic acid amides / Secondary alcohols
show 8 more
Substituents
1,2-aminoalcohol / 2-heteroaryl carboxamide / 2-piperidinecarboxamide / Alcohol / Amine / Amino acid or derivatives / Amphetamine or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle
show 26 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
quinolines, L-asparagine derivative (CHEBI:63621)

Chemical Identifiers

UNII
L3JE09KZ2F
CAS number
127779-20-8
InChI Key
QWAXKHKRTORLEM-UGJKXSETSA-N
InChI
InChI=1S/C38H50N6O5/c1-38(2,3)43-37(49)32-20-26-14-7-8-15-27(26)22-44(32)23-33(45)30(19-24-11-5-4-6-12-24)41-36(48)31(21-34(39)46)42-35(47)29-18-17-25-13-9-10-16-28(25)40-29/h4-6,9-13,16-18,26-27,30-33,45H,7-8,14-15,19-23H2,1-3H3,(H2,39,46)(H,41,48)(H,42,47)(H,43,49)/t26-,27+,30-,31-,32-,33+/m0/s1
IUPAC Name
(2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide
SMILES
[H][[email protected]@]12CCCC[[email protected]]1([H])CN(C[[email protected]@H](O)[[email protected]](CC1=CC=CC=C1)NC(=O)[[email protected]](CC(N)=O)NC(=O)C1=NC3=C(C=CC=C3)C=C1)[[email protected]@H](C2)C(=O)NC(C)(C)C

References

Synthesis Reference
US5196438
General References
  1. Forestier F, de Renty P, Peytavin G, Dohin E, Farinotti R, Mandelbrot L: Maternal-fetal transfer of saquinavir studied in the ex vivo placental perfusion model. Am J Obstet Gynecol. 2001 Jul;185(1):178-81. [PubMed:11483925]
  2. De Clercq E: The history of antiretrovirals: key discoveries over the past 25 years. Rev Med Virol. 2009 Sep;19(5):287-99. doi: 10.1002/rmv.624. [PubMed:19714702]
  3. Kupferschmidt HH, Fattinger KE, Ha HR, Follath F, Krahenbuhl S: Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br J Clin Pharmacol. 1998 Apr;45(4):355-9. doi: 10.1046/j.1365-2125.1998.t01-1-00687.x. [PubMed:9578182]
  4. Sundquist WI, Krausslich HG: HIV-1 assembly, budding, and maturation. Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006924. doi: 10.1101/cshperspect.a006924. [PubMed:22762019]
  5. De Clercq E: Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents. 2009 Apr;33(4):307-20. doi: 10.1016/j.ijantimicag.2008.10.010. Epub 2008 Dec 23. [PubMed:19108994]
  6. FDA Approved Drug Products: Invirase (saquinavir mesylate) oral tablets [Link]
  7. Health Canada Product Monograph: Invirase (saquinavir mesylate) for oral administration [Link]
  8. CaymanChem: Saquinavir MSDS [Link]
KEGG Drug
D00429
PubChem Compound
441243
PubChem Substance
46508726
ChemSpider
390016
BindingDB
519
RxNav
83395
ChEBI
63621
ChEMBL
CHEMBL114
ZINC
ZINC000003914596
Therapeutic Targets Database
DAP000171
PharmGKB
PA451305
PDBe Ligand
ROC
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Saquinavir
AHFS Codes
  • 08:18.08.08 — HIV Protease Inhibitors
PDB Entries
1c6z / 1fb7 / 1hxb / 2nmy / 2nmz / 2nnk / 2nnp / 3cyx / 3d1x / 3d1y
show 17 more
FDA label
Download (362 KB)
MSDS
Download (15.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedDiagnosticCardiovascular Heart Disease / HIV-Associated Lipodystrophy Syndrome1
4CompletedPreventionHuman Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentHealthy Volunteers / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections6
3CompletedNot AvailableDirectly Observed Therapy / Human Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentAIDS-Associated Nephropathy / Human Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections11
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections22
2CompletedTreatmentIDV Associated Nephrotoxicity1
2CompletedTreatmentSarcomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • A-S Medication Solutions LLC
  • F Hoffmann La Roche Ltd.
  • F Hoffmann-La Roche Ltd.
  • Pharmaceutical Utilization Management Program VA Inc.
  • Physicians Total Care Inc.
  • R.P. Scherer GmbH and Co. KG
Dosage Forms
FormRouteStrength
Capsule, liquid filledOral200 mg/1
Capsule200 MG
CapsuleOral200 mg
CapsuleOral200 mg/1
TabletOral500 mg
Tablet, film coatedOral500 mg
Tablet, film coatedOral500 mg/1
CapsuleOral
Tablet, coatedOral500 mg
Prices
Unit descriptionCostUnit
Invirase 500 mg tablet8.72USD tablet
Invirase 200 mg capsule3.87USD capsule
Fortovase 200 mg capsule1.46USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5196438No1993-03-232010-11-19US flag
CA2224125No2004-09-282016-06-04Canada flag
CA2030433No1997-10-212010-11-21Canada flag
US6352717Yes2002-03-052020-05-16US flag
US6008228Yes1999-12-282015-12-06US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)349.84 °CNot Available
water solubilityInsolubleNot Available
logP3.8Not Available
Caco2 permeability-6.26ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility0.00247 mg/mLALOGPS
logP4.04ALOGPS
logP3.16ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)13.61ChemAxon
pKa (Strongest Basic)8.47ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area166.75 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity186.67 m3·mol-1ChemAxon
Polarizability73.76 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.7774
Blood Brain Barrier-0.9949
Caco-2 permeable-0.8957
P-glycoprotein substrateSubstrate0.9048
P-glycoprotein inhibitor IInhibitor0.8563
P-glycoprotein inhibitor IIInhibitor0.5195
Renal organic cation transporterNon-inhibitor0.8612
CYP450 2C9 substrateNon-substrate0.8593
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateSubstrate0.7406
CYP450 1A2 substrateNon-inhibitor0.8729
CYP450 2C9 inhibitorNon-inhibitor0.7442
CYP450 2D6 inhibitorNon-inhibitor0.8536
CYP450 2C19 inhibitorNon-inhibitor0.7124
CYP450 3A4 inhibitorInhibitor0.5219
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9053
Ames testNon AMES toxic0.8489
CarcinogenicityNon-carcinogens0.865
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6007 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9687
hERG inhibition (predictor II)Inhibitor0.8153
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Aspartic-type endopeptidase activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72874
Uniprot Name
Pol polyprotein
Molecular Weight
10778.7 Da
References
  1. Wittayanarakul K, Hannongbua S, Feig M: Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors. J Comput Chem. 2008 Apr 15;29(5):673-85. [PubMed:17849388]
  2. Dandache S, Sevigny G, Yelle J, Stranix BR, Parkin N, Schapiro JM, Wainberg MA, Wu JJ: In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2007 Nov;51(11):4036-43. Epub 2007 Jul 16. [PubMed:17638694]
  3. Dandache S, Coburn CA, Oliveira M, Allison TJ, Holloway MK, Wu JJ, Stranix BR, Panchal C, Wainberg MA, Vacca JP: PL-100, a novel HIV-1 protease inhibitor displaying a high genetic barrier to resistance: an in vitro selection study. J Med Virol. 2008 Dec;80(12):2053-63. doi: 10.1002/jmv.21329. [PubMed:19040279]
  4. Rhee SY, Taylor J, Fessel WJ, Kaufman D, Towner W, Troia P, Ruane P, Hellinger J, Shirvani V, Zolopa A, Shafer RW: HIV-1 protease mutations and protease inhibitor cross-resistance. Antimicrob Agents Chemother. 2010 Oct;54(10):4253-61. doi: 10.1128/AAC.00574-10. Epub 2010 Jul 26. [PubMed:20660676]
  5. Alcaro S, Artese A, Ceccherini-Silberstein F, Ortuso F, Perno CF, Sing T, Svicher V: Molecular dynamics and free energy studies on the wild-type and mutated HIV-1 protease complexed with four approved drugs: mechanism of binding and drug resistance. J Chem Inf Model. 2009 Jul;49(7):1751-61. doi: 10.1021/ci900012k. [PubMed:19537723]
  6. Vella S, Lazzarin A, Carosi G, Sinicco A, Armignacco O, Angarano G, Andreoni M, Tambussi G, Chiodera A, Floridia M, Scaccabarozzi S, Facey K, Duncan I, Boudes P, Bragman K: A randomized controlled trial of a protease inhibitor (saquinavir) in combination with zidovudine in previously untreated patients with advanced HIV infection. Antivir Ther. 1996 Aug;1(3):129-40. [PubMed:11322246]
  7. Hoetelmans RM, Meenhorst PL, Mulder JW, Burger DM, Koks CH, Beijnen JH: Clinical pharmacology of HIV protease inhibitors: focus on saquinavir, indinavir, and ritonavir. Pharm World Sci. 1997 Aug;19(4):159-75. [PubMed:9297727]
  8. FDA Approved Drug Products: Invirase (saquinavir mesylate) oral tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxygen binding
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
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Granfors MT, Wang JS, Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT: Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):79-85. doi: 10.1111/j.1742-7843.2006.pto_249.x. [PubMed:16433896]
  2. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Granfors MT, Wang JS, Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT: Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):79-85. doi: 10.1111/j.1742-7843.2006.pto_249.x. [PubMed:16433896]
  2. Frohlich M, Hoffmann MM, Burhenne J, Mikus G, Weiss J, Haefeli WE: Association of the CYP3A5 A6986G (CYP3A5*3) polymorphism with saquinavir pharmacokinetics. Br J Clin Pharmacol. 2004 Oct;58(4):443-4. doi: 10.1111/j.1365-2125.2004.02159.x. [PubMed:15373940]
  3. Josephson F, Allqvist A, Janabi M, Sayi J, Aklillu E, Jande M, Mahindi M, Burhenne J, Bottiger Y, Gustafsson LL, Haefeli WE, Bertilsson L: CYP3A5 genotype has an impact on the metabolism of the HIV protease inhibitor saquinavir. Clin Pharmacol Ther. 2007 May;81(5):708-12. doi: 10.1038/sj.clpt.6100117. Epub 2007 Feb 28. [PubMed:17329995]
  4. Flockhart Table of Drug Interactions [Link]
Details
3. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33. [PubMed:10490933]
  3. Eagling VA, Wiltshire H, Whitcombe IW, Back DJ: CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica. 2002 Jan;32(1):1-17. doi: 10.1080/00498250110085845. [PubMed:11824416]
  4. Schmitt C, Hofmann C, Riek M, Patel A, Zwanziger E: Effect of saquinavir-ritonavir on cytochrome P450 3A4 activity in healthy volunteers using midazolam as a probe. Pharmacotherapy. 2009 Oct;29(10):1175-81. doi: 10.1592/phco.29.10.1175. [PubMed:19792991]
  5. Flockhart Table of Drug Interactions [Link]
  6. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [PubMed:26721703]
  2. Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL: Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther. 2007 Aug;82(2):197-203. doi: 10.1038/sj.clpt.6100122. Epub 2007 Mar 14. [PubMed:17361129]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. von Moltke LL, Greenblatt DJ, Duan SX, Daily JP, Harmatz JS, Shader RI: Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo. J Pharm Sci. 1998 Oct;87(10):1184-9. doi: 10.1021/js980197h. [PubMed:9758674]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Holladay JW, Dewey MJ, Michniak BB, Wiltshire H, Halberg DL, Weigl P, Liang Z, Halifax K, Lindup WE, Back DJ: Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir. Drug Metab Dispos. 2001 Mar;29(3):299-303. [PubMed:11181499]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Holladay JW, Dewey MJ, Michniak BB, Wiltshire H, Halberg DL, Weigl P, Liang Z, Halifax K, Lindup WE, Back DJ: Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir. Drug Metab Dispos. 2001 Mar;29(3):299-303. [PubMed:11181499]

Transporters

Details
1. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Perloff MD, von Moltke LL, Fahey JM, Daily JP, Greenblatt DJ: Induction of P-glycoprotein expression by HIV protease inhibitors in cell culture. AIDS. 2000 Jun 16;14(9):1287-9. [PubMed:10894301]
  2. Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB: Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos. 2000 Jun;28(6):655-60. [PubMed:10820137]
  3. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [PubMed:12699389]
  4. Kim AE, Dintaman JM, Waddell DS, Silverman JA: Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein. J Pharmacol Exp Ther. 1998 Sep;286(3):1439-45. [PubMed:9732409]
  5. Huisman MT, Smit JW, Wiltshire HR, Hoetelmans RM, Beijnen JH, Schinkel AH: P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. Mol Pharmacol. 2001 Apr;59(4):806-13. [PubMed:11259625]
  6. Troutman MD, Thakker DR: Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm Res. 2003 Aug;20(8):1210-24. [PubMed:12948019]
  7. Eagling VA, Profit L, Back DJ: Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol. 1999 Oct;48(4):543-52. [PubMed:10583025]
  8. Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G: Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004 May;21(5):819-26. [PubMed:15180340]
  9. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  10. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. Zhang L, Gorset W, Washington CB, Blaschke TF, Kroetz DL, Giacomini KM: Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system. Drug Metab Dispos. 2000 Mar;28(3):329-34. [PubMed:10681378]
  2. Moss DM, Liptrott NJ, Siccardi M, Owen A: Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter. Front Pharmacol. 2015 Apr 10;6:78. doi: 10.3389/fphar.2015.00078. eCollection 2015. [PubMed:25914645]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibit...
Gene Name
SLCO1A2
Uniprot ID
P46721
Uniprot Name
Solute carrier organic anion transporter family member 1A2
Molecular Weight
74144.105 Da
References
  1. Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB: OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos. 1999 Aug;27(8):866-71. [PubMed:10421612]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Gupta A, Zhang Y, Unadkat JD, Mao Q: HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 2004 Jul;310(1):334-41. Epub 2004 Mar 8. [PubMed:15007102]
  2. Janneh O, Owen A, Chandler B, Hartkoorn RC, Hart CA, Bray PG, Ward SA, Back DJ, Khoo SH: Modulation of the intracellular accumulation of saquinavir in peripheral blood mononuclear cells by inhibitors of MRP1, MRP2, P-gp and BCRP. AIDS. 2005 Dec 2;19(18):2097-102. [PubMed:16284458]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Tirona RG, Leake BF, Wolkoff AW, Kim RB: Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther. 2003 Jan;304(1):223-8. [PubMed:12490595]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Transporter activity
Specific Function
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotre...
Gene Name
ABCC1
Uniprot ID
P33527
Uniprot Name
Multidrug resistance-associated protein 1
Molecular Weight
171589.5 Da
References
  1. Williams GC, Liu A, Knipp G, Sinko PJ: Direct evidence that saquinavir is transported by multidrug resistance-associated protein (MRP1) and canalicular multispecific organic anion transporter (MRP2). Antimicrob Agents Chemother. 2002 Nov;46(11):3456-62. [PubMed:12384350]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Williams GC, Liu A, Knipp G, Sinko PJ: Direct evidence that saquinavir is transported by multidrug resistance-associated protein (MRP1) and canalicular multispecific organic anion transporter (MRP2). Antimicrob Agents Chemother. 2002 Nov;46(11):3456-62. [PubMed:12384350]
  2. Huisman MT, Smit JW, Crommentuyn KM, Zelcer N, Wiltshire HR, Beijnen JH, Schinkel AH: Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS. 2002 Nov 22;16(17):2295-301. [PubMed:12441801]
  3. Zelcer N, Huisman MT, Reid G, Wielinga P, Breedveld P, Kuil A, Knipscheer P, Schellens JH, Schinkel AH, Borst P: Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2). J Biol Chem. 2003 Jun 27;278(26):23538-44. Epub 2003 Apr 17. [PubMed:12702717]
  4. Honda Y, Ushigome F, Koyabu N, Morimoto S, Shoyama Y, Uchiumi T, Kuwano M, Ohtani H, Sawada Y: Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux. Br J Pharmacol. 2004 Dec;143(7):856-64. Epub 2004 Oct 25. [PubMed:15504753]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. Annaert P, Ye ZW, Stieger B, Augustijns P: Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica. 2010 Mar;40(3):163-76. doi: 10.3109/00498250903509375. [PubMed:20102298]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P: Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6. [PubMed:24014644]

Drug created on June 13, 2005 07:24 / Updated on September 25, 2020 15:13

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