Pre-systemic hepatic metabolism

Where it participates (unsigned role)

1. In man absorption from the gastrointestinal tract was essentially complete with time to maximum concentration at approximately one hour or less, bioavailability was attenuated by pre-systemic hepatic metabolism in all species, the elimination half-life in man was 3.7 hours, the majority of radioactivity was excreted in faeces with no unchanged drug detected in human excreta, five principal metabolic pathways operated in all species including piperazine N-demethylation, and following oral doses the areas under the curve for the piperazine N-desmethyl and N,N-desethyl metabolites were 55 and 27% that of the parent compound.

   Sildenafil → N-desmethyl sildenafil / UK-103,320 source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10219969.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58", "start_char": 0, "end_char": 1621, "text_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58"}

   experimental_model

   Pharmacokinetics after single intravenous and oral doses of labelled and unlabelled drug across five species

   exposure

   Carbon-14 labelled sildenafil with excretion balance and metabolite profiling

   limitations

   Cross-species pharmacokinetics with a mass balance. Single doses.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Mouse, rat, rabbit, dog and human

   plain_language

   It is absorbed completely, cut down by the liver on the way through, and the main breakdown product reaches about half the parent exposure.

   primary_references

   [sil-p10219969] Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. (1999). https://pubmed.ncbi.nlm.nih.gov/10219969/ DOI: 10.1080/004982599238687

   tissue_or_cell_type

   Whole body

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 444–455

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pharmacokinetics after single intravenous and oral doses of labelled and unlabelled drug across five species · source_derived_draft · unverified_draft

   ### sil-handling-and-metabolites In man absorption from the gastrointestinal tract was essentially complete with time to maximum concentration at approximately one hour or less, bioavailability was attenuated by pre-systemic hepatic metabolism in all species, the elimination half-life in man was 3.7 hours, the majority of radioactivity was excreted in faeces with no unchanged drug detected in human excreta, five principal metabolic pathways operated in all species including piperazine N-demethylation, and following oral doses the areas under the curve for the piperazine N-desmethyl and N,N-desethyl metabolites were 55 and 27% that of the parent compound. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It is absorbed completely, cut down by the liver on the way through, and the main breakdown product reaches about half the parent exposure. organism: Mouse, rat, rabbit, dog and human tissue_or_cell_type: Whole body experimental_model: Pharmacokinetics after single intravenous and oral doses of labelled and unlabelled drug across five species limitations: Cross-species pharmacokinetics with a mass balance. Single doses. exposure: Carbon-14 labelled sildenafil with excretion balance and metabolite profiling evidence_span: {"source_cache": "artifacts/sildenafil-research/10219969.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58", "start_char": 0, "end_char": 1621, "text_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58"} [sil-p10219969] Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. (1999). https://pubmed.ncbi.nlm.nih.gov/10219969/ DOI: 10.1080/004982599238687

   Complete structured claim and evidence

2. In six HIV-infected patients at steady state on indinavir a single 25 milligram dose of sildenafil did not significantly alter plasma indinavir concentrations, but the geometric mean area under the sildenafil concentration curve of 1631 nanograms per millilitre hour was 4.4 times higher than data from historical controls given either 50 or 100 milligrams and dose normalised to 25 milligrams, and in a parallel study indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro with a half-maximal inhibitory concentration of 0.39 micromolar, so that the mechanism of the increase is inhibition of hepatic metabolism and a lower starting dose may be more appropriate in this setting.

   Indinavir → Sildenafil source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   machinery_impairment Imported condition classification; unverified.

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10546851.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504", "start_char": 0, "end_char": 2556, "text_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504"}

   experimental_model

   Open pharmacokinetic study in six patients at steady state on a protease inhibitor, with a parallel in vitro metabolism arm

   exposure

   A single 25 milligram dose of sildenafil added to steady-state indinavir, with plasma sampling to eight hours

   limitations

   Six patients and no concurrent control group: the sildenafil exposure is compared with dose-normalised historical controls rather than with the same patients off indinavir.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Human

   plain_language

   A drug that blocks the same liver enzyme left more than four times as much of it in the blood.

   primary_references

   [sil-p10546851] Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. (1999). https://pubmed.ncbi.nlm.nih.gov/10546851/ DOI: 10.1097/00002030-199910220-00001

   tissue_or_cell_type

   Systemic circulation and liver microsomes

   trigger_kind

   machinery_impairment Imported condition classification; unverified.

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 470–481

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Open pharmacokinetic study in six patients at steady state on a protease inhibitor, with a parallel in vitro metabolism arm · source_derived_draft · unverified_draft

   ### sil-protease-inhibitor-quadruples-exposure In six HIV-infected patients at steady state on indinavir a single 25 milligram dose of sildenafil did not significantly alter plasma indinavir concentrations, but the geometric mean area under the sildenafil concentration curve of 1631 nanograms per millilitre hour was 4.4 times higher than data from historical controls given either 50 or 100 milligrams and dose normalised to 25 milligrams, and in a parallel study indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro with a half-maximal inhibitory concentration of 0.39 micromolar, so that the mechanism of the increase is inhibition of hepatic metabolism and a lower starting dose may be more appropriate in this setting. Condition category: machinery_impairment nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: A drug that blocks the same liver enzyme left more than four times as much of it in the blood. organism: Human tissue_or_cell_type: Systemic circulation and liver microsomes experimental_model: Open pharmacokinetic study in six patients at steady state on a protease inhibitor, with a parallel in vitro metabolism arm limitations: Six patients and no concurrent control group: the sildenafil exposure is compared with dose-normalised historical controls rather than with the same patients off indinavir. exposure: A single 25 milligram dose of sildenafil added to steady-state indinavir, with plasma sampling to eight hours evidence_span: {"source_cache": "artifacts/sildenafil-research/10546851.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504", "start_char": 0, "end_char": 2556, "text_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504"} [sil-p10546851] Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. (1999). https://pubmed.ncbi.nlm.nih.gov/10546851/ DOI: 10.1097/00002030-199910220-00001

   Complete structured claim and evidence