Table 2:

Pharmacokinetics, gastrointestinal side effects and dosing of PAH-specific medications in liver disease

Medication	Metabolism	Excretion^	GI side effects > 1%	Dosing of PHA medications by degree of liver impairment
Sildenafil PO	Hepatic via CYP3A4 (major) and CYP2C9 (minor route).	Feces: 80% Urine: 13%	Dyspepsia, diarrhea, gastritis, nausea, increased liver enzymes	C-P A, B: No adjustment C-P C: Not studied
Tadalafil PO	Hepatic, via CYP3A4	Feces: 61% Urine: 36%	Dyspepsia, nausea, GERD, abdominal pain, diarrhea, gastroenteritis, dysphagia, abnormal liver function tests.	C-P A, B: Use with caution; consider initial dose of 20 mg once daily C-P C: Not studied
Riociguat PO	Hepatic via CYP1A1, CYP3A, CYP2C8 and CYP2J2.	Feces: 53% Urine: 40%	Dyspepsia, nausea, diarrhea, vomiting, gastritis, constipation, GERD	C-P A, B: No adjustments CP C: Not studied
Bosentan PO	Hepatic via CYP2C9 and CYP3A4 to three primary metabolites.	Feces: mainly Urine: <3%	Increased in AST and ALT	C-P A: No adjustment  C-P B,C: Avoid use
Ambrisentan PO	Hepatic via CYP3A4, CYP2C19, and UGT 1A9S, 2B7S, and 1A3S	Feces: mainly	Dyspepsia	C-P A: No adjustment  C-P B, C: Use not recommended.
Macitentan PO	Hepatic via CYP3A4 (major) and CYP2C19	Feces: 24% Urine: 50%	Increased liver enzymes.	No dosage adjustments provided.
Epoprostenol IV	Rapidly hydrolyzed	Feces: 4% Urine: 84%	Nausea, vomiting, anorexia, diarrhea.	No dosage adjustments provided.
Treprostinil SQ / IV	Hepatic via CYP2C8	Feces: 13% Urine: 79%	Diarrhea, nausea.	C-P A, B: Use with caution and titrate slowly. CP C: No dosage adjustments provided. Use with caution and titrate slowly.
Treprostinil inh	Hepatic via CYP2C8	Feces: 13% Urine: 79%	Diarrhea, nausea.	No dosage adjustments provided. Use with caution and titrate slowly.
Treprostinil PO	Hepatic via CYP2C8	Feces: 13% Urine: 79%	Diarrhea, nausea.	C-P A: Use with caution and titrate slowly. C-P B: Avoid use. C-P C: Use is contraindicated.
Selexipag PO	Hepatic via CYP3A4, CYP2C8, UGT1A3 and UGT2B7.	Feces: 93% Urine: -	Diarrhea, nausea, vomiting, decreased appetite	C-P A: No dosage adjustment necessary. C-P B: Once daily. C-P C: Avoid use
Iloprost inh	Hepatic via beta oxidation of the carboxyl side chain	Feces: 12% Urine: 68%	Nausea, vomiting, glossalgia	CP A: No dosage adjustment necessary. C-P B, C: Consider increasing dosing interval

^*Data was obtained from Lexicomp Online (http://online.lexi.com/lco/action/home), Wolters Kluwer, accessed in October 2017.

^{^}Excretion percentages are approximate.

Abbreviations: ALT: alanine aminotransferase, AST: aspartate aminotransferase, C-P: Child-Pugh, CYP: cytochrome P, IV: intravenous, PO: orally, SQ: subcutaneous, UGT: uridine 5’-diphosphate glucuronosyltransferases.