CYP3A4 drug clearance twin

hepatocyte, alive: the cell keeps working while you watch. Every motion runs at a rate from a source, and the panel below drives it.

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Control panel

One hepatocyte, alive: glycogen fills and empties on a measured feeding cycle, CYP3A4 clears substrate, bile leaves at the canaliculus, and a hepatectomy rebuilds the cell. The budget bar below is the CYP3A4 intrinsic clearance.

CYP3A4 CLint per gram liver

271 uL/min/g

24.7 to 2,148 uL/min/g across the sourced ranges. No sourced capacity for this quantity, so the bar places this cell between the smallest and the largest the sourced ranges allow.

Intrinsic hepatic clearance per gram of liver; the product the hepatocyte population delivers to a pharmacokinetic model. Sustained by CYP3A4 enzyme density and substrate affinity.

source 1source 2,

Inputs

15 to 82 pmol/min · human hepatocytes, cryopreserved · luminescent LIPA substrate assay with ketoconazole CYP3A4 confirmation · Li AP 2009 Drug Metab Dispos · source

Vmax 41 pmol/min per million hepatocytes; thin: single batch; slider spans a 2-fold range around the reported value

5 to 45 uM · human hepatocytes, cryopreserved · Michaelis-Menten fit of LIPA metabolism time course · Li AP 2009 Drug Metab Dispos · source

apparent Km 15 uM for LIPA in human hepatocytes; slider covers the range where competitive inhibitors raise apparent Km 3-fold

74 to 131 million/g · human liver, multiple donors · meta-analysis of cell isolation studies · Barter ZE et al. 2007 Curr Drug Metab · source

weighted geometric mean 99 million cells per gram liver (95% CI 74-131)

1 to 100 uM · human hepatocytes, cryopreserved · Michaelis-Menten fit of LIPA metabolism time course · Li AP 2009 Drug Metab Dispos · source

apparent Km 15 uM; slider spans 1-100 uM covering sub-Km through saturating concentrations, matching the assay's reported substrate range

1 to 2 x baseline · MOUSE, cannulated bile duct · bile collection, cMoat/mrp2 transporter induction by 2,4,5-T herbicide · Wielandt AM 1999 Biochem J · source

control arm 1.13 ul/min/g (factor 1.0); herbicide arm 2.23 ul/min/g (factor ~1.97); slider covers the measured range

7.6 to 9.1 % · HUMAN, perfusion-fixed biopsy · scanning electron microscopy with Texture Analysing System (TAS); n=13 normal biopsies · Horn T 1986, Liver · source

verbatim: 'Increasing porosity towards the terminal hepatic vein was found (9.1% in zone 3 vs. 7.6% in zone 1 (p less than 0.05))'; density 19.2 per um2 in zone 1, 23.5 per um2 in zone 3; slider spans the measured zonal gradient

Readouts

CLint per million cells
2.73 uL/min
0.333 to 16.4 uL/min propagated
human hepatocytes · Michaelis-Menten CLint = Vmax / Km; uM equals pmol/uL so units cancel to uL/min  · source 1
Interval from evaluating at the ends of each input range; assumes the formula moves one way in each input.
CLint per gram liver
271 uL/min/g
24.7 to 2,148 uL/min/g propagated
human · per-cell CLint scaled by hepatocellularity from Barter 2007 meta-analysis  · source 1 · source 2
Interval from evaluating at the ends of each input range; assumes the formula moves one way in each input.

Withheld

Space of Disse width
PMID 3088829 (Sztark 1986) reports volume fractions for endothelial cells (8.2%) and perisinusoidal cells / Ito cells (4.7%) of sinusoid volume — not the width of the extracellular Disse space in um. No abstract in the sweep states the Disse space width in um for human liver. Range and default were invented from a misread fraction and an uncited sinusoid diameter. Requires a human EM morphometry abstract with the measured width before shipping. Sheet standoff position in the drawing is illustrative and marked as such.
Unbound plasma fraction
Unbound fraction in plasma is substrate-specific and cannot be given a cell-level default from a verified hepatocyte abstract; include fu when predicting in vivo clearance for a named drug.

Sources

human hepatocytes, cryopreserved · luminescent substrate assay with CYP3A4 selective inhibitor
human liver, multiple donors · meta-analysis of hepatocellularity measurements from cell isolation studies

Research use only. Every number here is geometry on published ranges, not a measurement of any individual.

Substances tested 10

All substances →
Clofibrate fibrate, peroxisome proliferator
acts on PPAR-alpha driven peroxisomal beta-oxidation
Raises the peroxisome volume fraction in hepatocytes from 1.05 percent to 6.26 percent and the mitochondrial volume fraction from 22 percent to 29.5 percent. Also protected the animals against the toxic, hypoglycaemic and hypothermic effects of hypoglycin and pent-4-enoate, and completely prevented the ultrastructural damage hypoglycin caused.
dose: 0.5 percent clofibrate in the diet for 1 to 2 months  · rat, male adult  · ultrastructural morphometry with biochemical assay  · Van Hoof F 1985, Biochem J  · source
Hypoglycin plant toxin, inhibitor of beta-oxidation
acts on mitochondrial fatty acid beta-oxidation
Doubles the mitochondrial volume fraction in hepatocytes, from 22 percent to 44 percent, and cuts the peroxisome volume fraction from 1.05 percent to 0.26 percent. Hypoglycaemic and hypothermic.
dose: injected; the amount is not stated in the abstract  · rat  · ultrastructural morphometry  · Van Hoof F 1985, Biochem J  · source
Phenobarbital barbiturate, classical CYP inducer
acts on cytochrome P-450, mixed function oxygenase system
Increases hepatocyte size: the average volume of the largest sedimenting cell fraction rose to 16,725 um3 from 10,500 um3 previously reported in untreated animals, and the number of cells in the fast-sedimenting fractions also increased. Cytochrome P-450 was raised, and a gradient of P-450 concentration across cell sizes persisted, with a 6.8-fold range in cytochrome per cell. Density fell in cells of all sizes.
dose: 40 mg/kg intraperitoneally, twice daily, for 3 days  · rat  · sedimentation velocity analysis with electronic cell sizing and P-450 assay  · Sweeney GD 1978, J Lab Clin Med  · source
3-Methylcholanthrene polycyclic aromatic hydrocarbon, CYP1A inducer
acts on aryl hydrocarbon hydroxylase, CYP1A1 and P1-450
Unlike phenobarbital, caused no significant increase in the size or number of cells in the fast-sedimenting fractions, but made the discontinuity in density and volume characteristics markedly more pronounced. The P-450 gradient across cell sizes was less steep, 4.62-fold against phenobarbital's 6.8-fold.
dose: 50 mg/kg as a single injection  · rat  · sedimentation velocity analysis with enzyme assay  · Sweeney GD 1978, J Lab Clin Med  · source
Ketoconazole azole antifungal, CYP3A4-selective inhibitor
acts on CYP3A4
Concentration-dependent inhibition of CYP3A4-mediated luciferin-isopropyl acetal metabolism in human hepatocytes, with more than 50 percent inhibition already at the lowest concentration evaluated.
dose: more than 50 percent inhibition at 0.78 uM, the lowest concentration tested  · human, cryopreserved hepatocytes  · luminescent substrate assay  · Li AP 2009, Drug Metab Dispos  · source
1-Aminobenzotriazole (ABT) non-specific cytochrome P450 inhibitor
acts on cytochrome P450, broadly
Concentration-dependent inhibition of the same CYP3A4 reaction, more than 50 percent at the lowest concentration evaluated. Used here as the non-selective comparator that establishes the reaction is P450-dependent.
dose: more than 50 percent inhibition at 7.8 uM, the lowest concentration tested  · human, cryopreserved hepatocytes  · luminescent substrate assay  · Li AP 2009, Drug Metab Dispos  · source
Rifampicin rifamycin antibiotic, PXR agonist and CYP3A inducer
acts on CYP3A, measured as 6beta-hydroxytestosterone formation
Induced CYP3A activity 2.8-fold in cryopreserved human hepatocytes, from 57.2 to 157.7 pmol per well per minute, against 2.3-fold in non-frozen cells, from 115.8 to 269.1. Note the basal activity in cryopreserved cells is about half that of fresh cells, so the larger fold-change starts from a lower floor.
dose: not stated in the abstract  · human, cryopreserved and fresh hepatocytes on collagen gel  · enzyme induction assay in culture  · Kafert-Kasting S 2006, Toxicology  · source
Acetaminophen (paracetamol) analgesic, dose-dependent hepatotoxin
acts on covalent protein binding; a 50-kDa microsomal protein comigrating with CYP2E1
Covalent binding was confined to the centrilobular hepatocytes, which is the area of the ensuing necrosis. The zonal restriction of the binding, not the binding alone, is what matches the injury pattern: the regioisomer 3'-hydroxyacetanilide binds proteins at similar levels without causing toxicity.
dose: 250 mg/kg intraperitoneally  · mouse  · immunochemical staining with Western blot  · Salminen WF Jr 1998, Drug Metab Dispos  · source

Every row rests on a PubMed abstract read in full by hepato.site on 2026-09-13. A dose not stated in the abstract is written as such and never guessed. Doses were read off the abstract by hand rather than taken from the extracted rows, because the sweep's list handling was wrong until extractor 1.7 and a solidus fraction is still parsed as its denominator, so "1/2 mg/kg" reads as 2 mg/kg. Research reference, not medical advice.

Public datasets 10

GSE136103 single-cell RNA-seq Homo sapiens; Mus musculus
Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics
Ramachandran P et al. 2019, Nature  · paper  · public at NCBI GEO; NCBI data are free to use with attribution and carry no licence text of their own  · accession resolved 2026-09-13 via eutils esummary on db=gds
GSE135251 bulk RNA-seq Homo sapiens
TRANSCRIPTOMIC PROFILING ACROSS THE SPECTRUM OF NON-ALCOHOLIC FATTY LIVER DISEASE
Govaere O et al. 2020, Sci Transl Med  · paper  · public at NCBI GEO  · accession resolved 2026-09-13 via eutils esummary on db=gds
GSE126848 bulk RNA-seq Homo sapiens
HEPATIC TRANSCRIPTOME SIGNATURES IN PATIENTS WITH VARYING DEGREES OF NON-ALCOHOLIC FATTY LIVER DISEASE COMPARED TO HEALTHY NORMAL-WEIGHT INDIVIDUALS
Suppli MP et al. 2019, Am J Physiol Gastrointest Liver Physiol  · paper  · public at NCBI GEO  · accession resolved 2026-09-13 via eutils esummary on db=gds
GSE48452 microarray Homo sapiens
Human liver biopsy of different phases from control to NASH
Ahrens M et al. 2013, Cell Metab  · paper  · public at NCBI GEO  · accession resolved 2026-09-13 via eutils esummary on db=gds
GSE89632 microarray Homo sapiens
Genome-wide analysis of hepatic gene expression in patients with non-alcoholic fatty liver disease and in healthy donors in relation to hepatic fatty acid composition and other nutritional factors
Arendt BM et al. 2015, Hepatology  · paper  · public at NCBI GEO  · accession resolved 2026-09-13 via eutils esummary on db=gds
GSE149614 single-cell RNA-seq Homo sapiens
A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma
Lu Y et al. 2022, Nat Commun  · paper  · public at NCBI GEO  · accession resolved 2026-09-13 via eutils esummary on db=gds
GSE164760 microarray Homo sapiens
Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis
Pinyol R et al. 2021, J Hepatol  · paper  · public at NCBI GEO  · accession resolved 2026-09-13 via eutils esummary on db=gds
EMPIAR-10791 FIB-SEM volume electron microscopy, 8 nm isotropic, with per-class organelle segmentations Mus musculus
High resolution 3D imaging of liver subcellular architecture and its link to metabolic function
Parlakgül G, Hotamisligil GS et al. 2022, Nature  · paper  · CC0. The entry page's License field is the CC0 public domain deed, shown as the standard CC0 badge linking to that deed; there is no quotable licence sentence and the EMPIAR REST API returns no rights field. Read from the rendered page on 2026-09-12.  · accession resolved 2026-09-12, entry page and EMPIAR REST API
EMPIAR-12017 FIB-SEM, 8 nm, with mitochondrial instance segmentations Mus musculus
Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity
Parlakgül G et al. 2024, Nat Commun  · paper  · CC0 by EMPIAR policy. NOT individually verified on the entry page; read that page before any download.  · accession resolved 2026-09-12, title via EMPIAR REST API
EMPIAR-13356 volume electron microscopy Homo sapiens
Multiscale human liver tissue sample volume electron microscopy
EMPIAR depositor; no linked PubMed record  · CC0. The entry page's License field links to https://creativecommons.org/share-your-work/public-domain/cc0/ (same CC0 badge pattern as EMPIAR-10791). No linked PubMed record; depositor is Xing CX (ORCID 0000-0002-7959-6403). Read from the rendered page on 2026-09-13.  · accession resolved 2026-09-13, entry page

Public datasets bearing on the hepatocyte. Titles are reproduced exactly as GEO returns them, including GEO's own ALL CAPS for GSE126848 and GSE135251 and its double space in the GSE89632 title, so a reader can match this file against the record character for character. The seven GEO series were selected from 334 distinct accessions found in the 167,603-abstract sweep, on the criterion that the subject is human liver parenchyma rather than a single pathway. The three EMPIAR volumes did NOT come from that count: they came from the picture and licence research in work/hepato-site/twin-v2-pictures.md, which is why this file holds ten rows and the 334-minus-327 arithmetic accounts for only seven of them. Every accession, by either route, was resolved at its own endpoint before entering the file. Sample counts are GEO's n_samples field. Where GEO lists several papers for a series, the primary report is cited and a paper_note names the others.