A botanical constituent has to reach the body, and survive what it meets there, before anyone can call it active in people
Exposure, interactions through drug-metabolizing enzymes and transporters, the models used before human studies, the U.S. drug pathway for botanicals, and what EUTECNIQ would and would not do.
Status. EUTECNIQ has run no studies and has no laboratory. Qualified partners would perform human pharmacokinetic studies, bioanalysis and regulated nonclinical studies (platform plan).
Mueller et al., Clin Pharmacol Ther 2004; Moore et al., PNAS 2000; Salvia-Trujillo et al., Nanomaterials 2016, Table 2. Published results, not EUTECNIQ data.
Of six processes at the gut wall, two send a molecule back or change it before it reaches the blood
All six routes are shown. Select one to follow it.
Efflux and gut-wall metabolism can lower what reaches the blood even when absorption is good; the lymphatic route is the one that skips the liver.
Text version of the six routes, and three distinctions
The six routes, with the barrier letters used in the figure:
- Passive transcellular (MP). Lipophilic molecules diffuse across the cell membranes.
- Paracellular (TJ). Small hydrophilic molecules pass between cells through the tight junctions.
- Carrier-mediated uptake (AT). An uptake transporter moves the molecule into the cell.
- Efflux (ET). An efflux transporter such as P-glycoprotein pumps the molecule back into the lumen.
- Gut-wall metabolism (M). Enzymes in the enterocyte, such as CYP3A4 or conjugating enzymes, transform it; the metabolite may leave toward the blood or the lumen.
- Lymphatic route. Very lipophilic molecules can travel with chylomicrons into lymph, which bypasses the liver.
Portal blood carries what crosses the gut wall to the liver, where first-pass metabolism removes a further share before the systemic circulation, where exposure is measured as AUC and Cmax.
Three distinctions follow from these routes:
- Released is not absorbed. Bioaccessibility in a simulated gut is not systemic bioavailability, and exposure is not benefit.
- Interactions count as much as exposure. Some botanical constituents change how the body handles medicines, through enzymes and transporters.
- Disease intent means drug law. A study of disease treatment needs an IND, drug-quality supplies and a drug sponsor.
Oral bioavailability is a chain of fractions, and the weakest link sets the ceiling
Text version of the six stages
- DoseThe amount swallowed, in a defined form.
- BioaccessibleReleased from the matrix and dissolved or held in mixed micelles in the gut.
- Absorbed, FaCrosses the intestinal wall by passive or active transport.
- Escapes gut wall, FgNot metabolized or pumped back by enzymes and transporters in the enterocytes.
- Escapes liver, FhNot removed on the first pass through the liver.
- Systemic exposureMeasured in blood as AUC and Cmax, as parent compound and metabolites.
Show data
| Step | Remaining (% of dose) |
|---|---|
| Dose | 100 |
Method, assumptions and limits: bioavailability chain
- What it calculates
- The fraction of an oral dose that reaches the systemic circulation unchanged, and the highest value that fraction could reach if absorption were complete.
- Equation
- F = Fa·Fg·Fh; ceiling = Fg·Fh; loss at each step = remaining before the step × (1 − its fraction).
- Variables and units
- All three fractions are dimensionless, 0–1 (sliders in %, clamped to 0–100).
- Assumptions
- Linear (dose-independent) kinetics; the fractions act in sequence and independently; parent compound only. Real values depend on dose, formulation, food and the individual, and saturation of first-pass elimination can make them dose-dependent.
- What it does not establish
- It does not predict the bioavailability of any botanical constituent. It shows why a formulation that raises absorption cannot lift exposure above the ceiling set by first-pass metabolism, and why metabolites, not only the parent compound, may carry exposure.
- Verification
- Independent Python cases in
tests/numerics/ref/technologies-translational-research.pyat default, low and high settings.
Explanation, details and sources
After an oral dose, a constituent must be released and dissolved, cross the gut wall, escape metabolism in the gut wall and then in the liver. Oral bioavailability F is the product of the fraction absorbed (Fa), the fraction escaping gut-wall elimination (Fg) and the fraction escaping hepatic elimination (Fh).
Bioaccessibility is not bioavailability
Bioaccessibility is the share released and solubilized in the gut, measured with simulated digestion such as the INFOGEST protocol. Systemic bioavailability also depends on permeability and first-pass metabolism, so a large bioaccessibility gain can produce a small exposure gain, or none.
Brodkorb A, et al. Nat Protoc. 2019;14(4):991–1014. Varma et al. 2010.
Measure the right analyte
Hydrolyzing plasma samples before analysis adds conjugated metabolites to the free compound. Reviewers of curcumin studies call that practice inappropriate for quantifying blood curcumin, so any fold-increase in exposure must state whether total or free compound was measured.
Stohs SJ, et al. Molecules. 2020;25(6):1397. See Evidence and pharmacokinetics.
Some botanicals change how the body handles medicines, which can matter more than their own exposure
Data table
| Product | AUC₀–₂₄, % | Cmax, % | Ctrough, % |
|---|---|---|---|
| LI 160 extract, high dose, hyperforin-rich | −24.8 (−28.3 to −21.3) | −37 (−42 to −32) | −19 (−27 to −11) |
| Hypericum powder 4 g, comparable hyperforin | −26.6 (−37.3 to −15.9) | −38 (−48 to −18) | −19 (−27 to −10) |
| Hypericum powder 2 g, half the hyperforin | −17.7 (−21.6 to −13.7) | −21 (−40 to −2) | −13 (−21 to −5) |
| Hyperforin-free extract (Ze 117); 2 g powder without hyperforin; 1 g and 0.5 g powder; tea; juice; oil extract; placebo | No significant interaction (values not given in the abstract) | ||
Products without hyperforin, or with little of it, showed no significant effect on digoxin, so the plant name alone does not predict the interaction.
Text version of the examples
St. John's wort
St. John's wort induces hepatic drug metabolism through the pregnane X receptor, and hyperforin is the constituent responsible for inducing CYP3A4. NCCIH warns that it can weaken many medicines, including transplant, HIV and contraceptive drugs and warfarin.
Moore LB, et al. Proc Natl Acad Sci USA. 2000;97(13):7500–7502. Nahrstedt A, Butterweck V. J Nat Prod. 2010;73(5):1015–1021. NCCIH, May 2025.
Green tea
At high doses, green tea reduced blood levels, and therefore the effectiveness, of the beta-blocker nadolol.
NCCIH. Green Tea: Usefulness and Safety (February 2025).
Natural-product interaction research
The NIH-funded NaPDI Center lists the hurdles: large batch-to-batch variability in composition, limited pharmacokinetic knowledge of the constituents that cause interactions, and in vitro or animal models that do not always extrapolate to people.
Paine MF, Shen DD, McCune JS. Drug Metab Dispos. 2018;46(7):1041–1045.
Explanation, details and sources
Cytochrome P450 enzymes (CYPs) metabolize most drugs, and transporters such as P-glycoprotein move drugs across membranes. A constituent that induces or inhibits them can lower or raise the exposure to a co-administered medicine.
For drugs, ICH M12 (FDA final guidance, August 2024) sets out how enzyme- and transporter-mediated interaction studies are designed, run and interpreted, in vitro and in clinical studies. It is written for drug development; natural-product research often adapts it.
Each model answers one question; none of them, alone, predicts what happens in people
Text version: each model, its question, its limits and who would run it
| Model | Question it answers | Limits | Planned |
|---|---|---|---|
| Dissolution and release testing | How fast and how much is released from a dosage form under test conditions | Release is not absorption | Phase I |
| Static in vitro digestion (INFOGEST) | Bioaccessibility: release and solubilization in simulated oral, gastric and intestinal phases | No absorption, no metabolism, no feedback from the body | Phase I |
| Caco-2 cell monolayers | Permeability in both directions, passive and active transport | A colon-derived cell line; it does not reproduce first-pass metabolism in the gut wall and liver | Partner |
| Liver microsomes, hepatocytes, recombinant enzymes | Metabolic stability; potential to inhibit or induce CYPs | Needs constituent concentrations relevant to the gut or liver to mean anything clinically | Partner |
| Transporter-expressing cell systems | Whether a constituent is a substrate or inhibitor of a transporter | Same concentration question; one transporter at a time | Partner |
| In silico and PBPK models | Integrate the data above to predict exposure and interaction scenarios | Only as good as the measured inputs and the constituents chosen | Planned |
| Animal pharmacokinetics | Whole-body exposure and metabolites | Species differences in metabolism and transport | Partner |
| Human pharmacokinetic study | Exposure to parent compound and metabolites against a defined comparator | Exposure is not benefit; needs ethics review and informed consent | Partner |
| Human outcome study | Whether people benefit on a defined endpoint | A disease endpoint makes it a drug study needing an IND | Partner |
Brodkorb et al. 2019 (INFOGEST). Hubatsch I, Ragnarsson EGE, Artursson P. Nat Protoc. 2007;2(9):2111–2119 (Caco-2). ICH M12 Drug Interaction Studies, FDA final guidance, August 2024. Paine et al. 2018. Modeling is described on Computational science and AI.
Activity in a cell assay at a concentration the body never reaches is not evidence of an effect in people.
A botanical intended to treat or prevent disease is a drug, and the drug pathway is long, specific and regulated
Text version: when human research or manufacturing triggers drug requirements
| Situation | What applies | Status |
|---|---|---|
| A study of a supplement's effect on the structure or function of the body | No IND is required | Final guidance FDA IND guidance (2013), § VI.D.1 |
| A study of a supplement's ability to diagnose, cure, mitigate, treat or prevent a disease | An IND is required under 21 CFR Part 312 | Final guidance FDA IND guidance (2013), § VI.D.1 |
| A clinical study with safety endpoints only | Generally no IND; human-subject protection (21 CFR Parts 50 and 56) applies | Final guidance FDA NDI guidance (October 2026), footnote 20 |
| Nonclinical laboratory studies supporting an IND or NDA | Good laboratory practice, 21 CFR Part 58 | Regulation § 58.1, § 58.3(e) |
| Making a drug, including investigational supplies for drug studies | Drug cGMP, 21 CFR Parts 210 and 211, not the supplement cGMP of Part 111 | Regulation § 210.1, § 211.1, § 111.1 |
| Controlled trials of a drug product (other than phase 1) | Registration and results reporting for applicable clinical trials, 42 CFR Part 11 | Regulation § 11.22 |
FDA. Investigational New Drug Applications (INDs)—Determining Whether Human Research Studies Can Be Conducted Without an IND. September 2013; § VI.D.1 is not affected by the 2015 partial stay. FDA. NDI Identity and Safety Information guidance, final, October 2026. eCFR Titles 21 and 42, up to date as of October 21, 2026. A 2022 proposed rule on IND exemptions for lawfully marketed foods, supplements and cosmetics (87 FR 75536) has not been finalized. Details: Clinical research and Toxicology.
Explanation, details and sources
FDA describes botanical drug products as products that include or are derived from plant materials, algae, macroscopic fungi or combinations of them, intended for the diagnosis, cure, mitigation, treatment or prevention of disease. Highly purified substances are generally not considered botanical drugs.
Botanical Drug Development (December 2016)
FDA's final guidance gives recommendations on investigational new drug applications (INDs) and new drug applications (NDAs) for botanical drugs, and general information on the over-the-counter monograph system for botanicals.
FDA. Botanical Drug Development: Guidance for Industry. December 2016; docket FDA-2000-D-0103.
Four botanical prescription drugs
FDA states that four botanical products have been approved as prescription drugs: three under NDAs (sinecatechins, crofelemer and birch triterpenes) and one under a biologics license application (anacaulase-bcdb).
FDA. What Is a Botanical Drug? Content current as of September 3, 2026.
EUTECNIQ would generate the botanical science a drug developer needs, and leave drug development to drug developers
The proposed role is a scientific partner to companies that hold, or will hold, the regulatory responsibility.
Text version: would do and would not do
Characterization, exposure science and coordination
- Identity, composition and variability data on the botanical substance for a sponsor's chemistry, manufacturing and controls file.
- Dissolution, in vitro digestion and formulation studies in its own laboratory once built.
- Literature and interaction assessments, and pharmacokinetic study design with partner CROs.
- Modeling that combines measured inputs into exposure scenarios, labeled as models.
Drug manufacture, drug sponsorship or disease claims
- No drug manufacturing: no Parts 210/211 operations are proposed, including investigational supplies.
- No self-funded drug trials: EUTECNIQ would not sponsor an IND for its own account.
- No disease claims for supplements or cosmetics, on this site or in client work.
- No GLP studies in house: regulated nonclinical studies would go to GLP-compliant partners.
Explanation, details and sources
Founder-reported prior experience The founder reports involvement in three human clinical PK/PD programs for botanical products at a prior employer. These are not EUTECNIQ results; see Founder. Partnership models are described on Pharmaceutical partnerships.
Developing a botanical drug candidate or studying interactions?
EUTECNIQ is in formation and would discuss how characterization and exposure science could support a sponsor's program.