Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI19SPMY7)
  Drug Name Ritonavir Drug Info Ambrisentan Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Anti-Hiv Agents Agents For Pulmonary Hypertension
  Structure

 Mechanism of Ritonavir-Ambrisentan Interaction (Severity Level: Moderate)
     Transporter inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Ritonavir Ambrisentan
      Mechanism 1 OATP1B1 inhibitor OATP1B1 substrate
      Key Mechanism Factor 1
Factor Name Liver organic anion transporter 1
×
Structure Sequence
MDQNQHLNKTAEAQPSENKKTRYCNGLKMFLAALSLSFIAKTLGAIIMKSSIIHIERRFEISSSLVGFIDGSFEIGNLLVIVFVSYFGSKLHRPKLIGIGCFIMGIGGVLTALPHFFMGYYRYSKETNINSSENSTSTLSTCLINQILSLNRASPEIVGKGCLKESGSYMWIYVFMGNMLRGIGETPIVPLGLSYIDDFAKEGHSSLYLGILNAIAMIGPIIGFTLGSLFSKMYVDIGYVDLSTIRITPTDSRWVGAWWLNFLVSGLFSIISSIPFFFLPQTPNKPQKERKASLSLHVLETNDEKDQTANLTNQGKNITKNVTGFFQSFKSILTNPLYVMFVLLTLLQVSSYIGAFTYVFKYVEQQYGQPSSKANILLGVITIPIFASGMFLGGYIIKKFKLNTVGIAKFSCFTAVMSLSFYLLYFFILCENKSVAGLTMTYDGNNPVTSHRDVPLSYCNSDCNCDESQWEPVCGNNGITYISPCLAGCKSSSGNKKPIVFYNCSCLEVTGLQNRNYSAHLGECPRDDACTRKFYFFVAIQVLNLFFSALGGTSHVMLIVKIVQPELKSLALGFHSMVIRALGGILAPIYFGALIDTTCIKWSTNNCGTRGSCRTYNSTSFSRVYLGLSSMLRVSSLVLYIILIYAMKKKYQEKDINASENGSVMDEANLESLNKNKHFVPSAGADSETHC
Gene Name OATP1B1
Uniprot ID SO1B1_HUMAN
KEGG Pathway hsa:10599
Protein Family Organo anion transporter (TC 2.A.60) family
Protein Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
    Click to Show/Hide
      Mechanism Description
  • Decreased clearance of Ambrisentan due to the transporter inhibition by Ritonavir 
      Mechanism 2 P-gp inhibitor P-gp substrate
      Key Mechanism Factor 2
Factor Name P-glycoprotein 1
×
Structure Sequence
MDLEGDRNGGAKKKNFFKLNNKSEKDKKEKKPTVSVFSMFRYSNWLDKLYMVVGTLAAIIHGAGLPLMMLVFGEMTDIFANAGNLEDLMSNITNRSDINDTGFFMNLEEDMTRYAYYYSGIGAGVLVAAYIQVSFWCLAAGRQIHKIRKQFFHAIMRQEIGWFDVHDVGELNTRLTDDVSKINEGIGDKIGMFFQSMATFFTGFIVGFTRGWKLTLVILAISPVLGLSAAVWAKILSSFTDKELLAYAKAGAVAEEVLAAIRTVIAFGGQKKELERYNKNLEEAKRIGIKKAITANISIGAAFLLIYASYALAFWYGTTLVLSGEYSIGQVLTVFFSVLIGAFSVGQASPSIEAFANARGAAYEIFKIIDNKPSIDSYSKSGHKPDNIKGNLEFRNVHFSYPSRKEVKILKGLNLKVQSGQTVALVGNSGCGKSTTVQLMQRLYDPTEGMVSVDGQDIRTINVRFLREIIGVVSQEPVLFATTIAENIRYGRENVTMDEIEKAVKEANAYDFIMKLPHKFDTLVGERGAQLSGGQKQRIAIARALVRNPKILLLDEATSALDTESEAVVQVALDKARKGRTTIVIAHRLSTVRNADVIAGFDDGVIVEKGNHDELMKEKGIYFKLVTMQTAGNEVELENAADESKSEIDALEMSSNDSRSSLIRKRSTRRSVRGSQAQDRKLSTKEALDESIPPVSFWRIMKLNLTEWPYFVVGVFCAIINGGLQPAFAIIFSKIIGVFTRIDDPETKRQNSNLFSLLFLALGIISFITFFLQGFTFGKAGEILTKRLRYMVFRSMLRQDVSWFDDPKNTTGALTTRLANDAAQVKGAIGSRLAVITQNIANLGTGIIISFIYGWQLTLLLLAIVPIIAIAGVVEMKMLSGQALKDKKELEGSGKIATEAIENFRTVVSLTQEQKFEHMYAQSLQVPYRNSLRKAHIFGITFSFTQAMMYFSYAGCFRFGAYLVAHKLMSFEDVLLVFSAVVFGAMAVGQVSSFAPDYAKAKISAAHIIMIIEKTPLIDSYSTEGLMPNTLEGNVTFGEVVFNYPTRPDIPVLQGLSLEVKKGQTLALVGSSGCGKSTVVQLLERFYDPLAGKVLLDGKEIKRLNVQWLRAHLGIVSQEPILFDCSIAENIAYGDNSRVVSQEEIVRAAKEANIHAFIESLPNKYSTKVGDKGTQLSGGQKQRIAIARALVRQPHILLLDEATSALDTESEKVVQEALDKAREGRTCIVIAHRLSTIQNADLIVVFQNGRVKEHGTHQQLLAQKGIYFSMVSVQAGTKRQ
Gene Name ABCB1
Uniprot ID MDR1_HUMAN
KEGG Pathway hsa:5243
Protein Family ABC transporter superfamily
Protein Function
Translocates drugs and phospholipids across the membrane (PubMed:8898203, PubMed:2897240, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:9038218).
    Click to Show/Hide
      Mechanism Description
  • Decreased clearance of Ambrisentan due to the transporter inhibition by Ritonavir 

Recommended Action
      Management Because ambrisentan is associated with dose-related hepatotoxicity, concomitant use with potent inhibitors of P-gp and/or OATP should be approached with caution. Patients should be advised to notify their physician if they experience signs and symptoms of liver injury such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

References
1 Product Information. Letairis (ambrisentan). Gilead Sciences, Foster City, CA.