Minoxidil Is a Prodrug: Sulfotransferase, Tretinoin, and the Responder Question

Minoxidil arrives at the follicle switched off. The molecule applied to the scalp is a prodrug, and sulfotransferase enzymes in the outer root sheath of the follicle convert it to minoxidil sulfate, the form that acts. That single fact, established in the pharmacology decades ago and made clinically useful only in the last ten years, explains the non-response rate to topical minoxidil, explains why tretinoin sits beside it in compounded solutions, and explains why a plucked hair follicle can now be assayed before a bottle is opened. Topical minoxidil at 2% and 5% is FDA-approved as an over-the-counter product; every combination solution in a compounded formulary is a prescription product prepared under section 503A, and no combination has an approved label of its own.

This article sets out the prodrug chemistry, the response literature built on the enzyme, the tretinoin story from its 1986 origin to the 2019 enzyme study and the 2026 review, what the approved product is and what a compounded solution is, and the rationale behind each ingredient in the combination solutions. It attributes every finding to the study that reported it, makes no claim about what any solution does to hair, and leaves the prescribing decision with the prescriber.

A key cut at the door: minoxidil needs the follicle to finish it

Minoxidil was developed as an oral antihypertensive, and hair growth was recorded as an adverse effect before anyone studied it as a topical agent, a history the 2019 review by Suchonwanit and colleagues in Drug Design, Development and Therapy sets out in full. The active species is minoxidil sulfate, produced from minoxidil by sulfotransferase enzymes, and in the scalp that conversion happens inside the follicle. An analogy that holds for the sequence and not for the biochemistry is a key blank that is cut at the door rather than at the locksmith: the bottle supplies the blank, and the follicle has to cut it before it turns anything.

A topical solution therefore depends on two things, the concentration applied and the enzymatic capacity of the follicles it reaches, and for decades the second was the neglected variable. The non-response rate to topical minoxidil was discussed in the context of adherence, formulation and disease severity, and a good part of it turned out to be enzymatic.

The enzyme predicts who responds, on the scalp and by mouth

Ramos and colleagues reported in Dermatologic Therapy in 2020 that sulfotransferase activity measured in plucked hair follicles predicted which women with pattern hair loss responded to topical minoxidil, which turned an explanation into a test. The same group reported in the Journal of the European Academy of Dermatology and Venereology in 2021 that genetic variants of the SULT1A1 enzyme predicted response to oral minoxidil, and Jimenez-Cauhe and colleagues reported in 2024 on follicular sulfotransferase activity and the effectiveness of oral minoxidil in androgenetic alopecia. Randolph and Tosti reviewed the oral route in the Journal of the American Academy of Dermatology in 2021, and a reader who wants the enzyme literature in its context should read that review beside the assay papers.

The clinical reading is straightforward and it is not a claim about any product. A patient whose follicles carry little of the enzyme is unlikely to convert much of what is applied, and the literature reports that the enzyme can be measured and, in some hands, induced.

Tretinoin is an enzyme inducer, and the pairing is older than the mechanism

Tretinoin enters the minoxidil story as an inducer of the enzyme rather than as a hair molecule in its own right. Sharma, Goren and colleagues reported in Dermatologic Therapy in 2019 that five days of topical tretinoin raised follicular sulfotransferase expression and converted 43% of subjects predicted by the enzyme assay to be minoxidil non-responders into responders, and Dhurat and colleagues reported a randomised trial of an enzyme-booster approach to topical minoxidil in the Journal of Cosmetic Dermatology in 2022. Those two studies are the mechanistic basis for the minoxidil and tretinoin solutions in compounded formularies.

The pairing is older than the mechanism. Bazzano and colleagues reported on topical tretinoin with minoxidil in the Journal of the American Academy of Dermatology in 1986, and the combination sat in dermatology practice for three decades on an empirical footing before the sulfotransferase work explained why it might matter. Maas and colleagues reviewed the whole co-therapy literature in Skin Appendage Disorders in 2026, and a reader who opens the 1986 report and the 2019 enzyme study is reading the same observation from opposite ends of a forty-year corridor.

The approved product and the compounded solution are different things

Topical minoxidil at 2% and 5% is FDA-approved as an over-the-counter product, and the 2017 meta-analysis by Adil and Godwin in the Journal of the American Academy of Dermatology reported that it outperformed placebo on hair count across pooled randomised trials. The 2022 network meta-analysis by Gupta and colleagues in JAMA Dermatology ranked minoxidil against the 5-alpha-reductase inhibitors in men, and the finasteride article in this series takes that ranking at its own level of detail. That is the approved product and its evidence.

A compounded solution that adds tretinoin to 5% minoxidil, or that adds finasteride, azelaic acid and ketoconazole, is a different product. It is prepared under section 503A of the Federal Food, Drug, and Cosmetic Act to an individual prescription, it carries a beyond-use date rather than a shelf life, and it has not been evaluated by the FDA for safety, effectiveness or quality, as the FDA’s own questions and answers on compounding state. Where a compounded solution contains finasteride, the FDA alert on compounded topical finasteride, discussed in full in the finasteride article, applies to it.

Each ingredient has a rationale; the combination has no trial

The table separates two things that marketing tends to merge. Each ingredient has a rationale in the literature, and for two of them the literature includes randomised trials of a two-ingredient solution. No trial of the four-ingredient combination has been published, and a page that presented the component studies as evidence for the combination would be making a claim the studies do not carry. Ketoconazole and azelaic acid have their own article later in this series, which takes the shampoo studies and the in vitro work at their own level of detail.

• Minoxidil is a prodrug; its active form is made in the follicle by sulfotransferase, and enzyme activity varies between people.
• Follicular sulfotransferase activity has been reported to predict response to topical minoxidil, and SULT1A1 variants to predict response to oral minoxidil.
• Tretinoin has been reported to induce the enzyme, which is the rationale for the minoxidil and tretinoin solution.
• Approved topical minoxidil is an over-the-counter product; every combination solution is a compounded prescription product with a beyond-use date.
• No trial of the four-ingredient solution exists; its ingredients are supported individually and at different levels.

Closing Observation

The minoxidil literature of the last decade is a literature about an enzyme, and it rewards the practice that reads it that way. The prodrug chemistry explains non-response, the follicle assay turns the explanation into a measurement, and the tretinoin studies show that the enzyme can be induced, which is why a 1986 pairing acquired a mechanism in 2019 and a review in 2026. The approved product has a meta-analysis and a network ranking behind it, and the compounded solutions have component rationales of very different strengths and no trial of the combination.

What the literature does not support is the reading that a longer ingredient list is a stronger product. A practice that keeps the enzyme in view will understand why two patients on the same bottle can diverge, will hold the approved product and the compounded solution in separate regulatory boxes, and will be considerably harder to sell a four-ingredient solution to on the strength of four separate rationales.