Routes of administration explained: how compounds reach the blood and the brain

What bioavailability means

Whether a supplement, a nootropic or a peptide works is not decided at the receptor alone. The compound first has to get there, and much of it is often lost on the way. Pharmacology captures this in a single term, bioavailability: the fraction of a dose that reaches the systemic circulation unchanged.

It is measured by comparing the blood concentration curve after the route being studied with the curve after an injection into a vein, specifically the areas under the two concentration-time curves ^[1]. Given intravenously, the entire dose enters the blood, so bioavailability is 100% by definition, and every other route is measured against it. When several sites of loss lie in series, such as the gut wall and the liver, bioavailability is the product of the fractions that get past each one ^[1]. If each lets half through, only a quarter arrives.

The route of administration therefore determines how much arrives, how fast and in what form. The animation shows the main routes schematically. The sections below explain the mechanism, typical use and limits of each route, each with a sourced example.

Oral: the long road through gut and liver

Swallowed compounds are mostly absorbed in the gut. Blood from the gut flows through the portal vein to the liver first, before it reaches the rest of the body. Enzymes in the gut wall and liver can break down part of the compound before then. This first-pass effect matters clinically above all when the fraction that escapes it is small and varies between people ^[1]. How strong it is depends on factors such as enzyme activity, binding to plasma proteins and gut motility. For some drugs it is so pronounced that swallowing them as a tablet is not an option, lidocaine and nitroglycerin among them ^[1].

Peptides face a second hurdle. In the digestive tract they are extensively degraded by protein-cleaving enzymes and poorly absorbed across the gut barrier ^[2]. How hard that hurdle is shows in the best-known exception: semaglutide, an analogue of the gut hormone GLP-1, is also used as a tablet for type 2 diabetes, the first GLP-1 receptor agonist available in this form ^[3].

The tablet contains the absorption enhancer SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate). Studies by the manufacturer in humans and dogs showed that semaglutide is absorbed not in the intestine, like most drugs, but in the stomach, and only in close proximity to the tablet surface. There, SNAC buffers stomach acid locally, protecting the peptide from enzymatic degradation, and briefly eases its passage through the cells of the gastric lining ^[2].

Even so, little arrives. A pharmacokinetic model based on several clinical pharmacology trials put bioavailability at 0.8% under the recommended dosing conditions. It rose with a longer fasting period after the dose and fell with more water. Within the same person it varied widely from dose to dose (variability 137%); only the long half-life largely evens this out with daily dosing ^[3]. In other words, more than 99% of the dose never reaches the circulation, and this for a peptide that was paired with an excipient specifically for this route.

For supplements, too, the mouth is often the bottleneck. In a dose-escalation study in 24 healthy people, no curcumin was detectable in serum at most dose levels after a single dose of a standardised curcumin extract; only two people from the two highest levels had low amounts in their blood ^[4]. What formulations change about this is covered in the curcumin profile (in German).

Sublingual and buccal: through the lining of the mouth

Under the tongue (sublingual) or in the cheek pouch (buccal) lies a richly vascularised mucosa. Whatever is absorbed there enters the systemic circulation directly, bypassing the gastrointestinal tract and the liver. For some drugs, this means a rapid onset of action ^[5].

The classic example is nitroglycerin, one of the most common drugs given through the oral mucosa ^[5]. Swallowed, it would be broken down in the liver to such an extent that a tablet for swallowing is not an option ^[1]. Here the route decides whether a drug can be used at all.

But the route does not work for every substance. Whether a compound crosses the oral mucosa depends on the properties of the mucosa and on the compound’s physicochemical properties. Many drugs have been studied for this route, yet few such products are on the market ^[5]. When a supplement is sold as “sublingual”, the key question is therefore whether uptake through the mucosa has been measured for that very substance, or whether it simply ends up being swallowed.

Intranasal: a shortcut to the brain?

The blood-brain barrier essentially admits only small, non-polar substances to the brain ^[6]. Intranasal delivery is therefore seen as a way around it: from the nasal cavity, compounds can travel along the olfactory and trigeminal nerves directly to the brain ^{[6], [7]}. This is being investigated mainly for large molecules such as proteins, for example in stroke, Parkinson’s or Alzheimer’s disease, in preclinical and clinical studies ^[6].

Two mechanisms are discussed. In the intracellular pathway, olfactory sensory cells take up the compound and carry it along their nerve fibres to the olfactory bulb, from where it can spread further. In the extracellular pathway, it passes between the cells of the nasal lining and along the nerve sheaths into the fluid-filled space around the brain ^[7]. Part of the dose is also absorbed into the blood ^[8].

How small the share reaching the brain can be is shown by one of the few measurements for a nootropic peptide. Russian researchers gave rats radiolabelled Semax into the nose. After two minutes, 0.093% of the administered radioactivity was found per gram of brain tissue; 80% of that was intact Semax, the rest breakdown products. The peptide was rapidly cleaved by enzymes, and the tripeptide Pro-Gly-Pro soon predominated in the samples ^[8].

Two caveats apply. The measurement comes from rats; it has not been made for Semax in humans. And the data reported in the abstract do not show how much of the radioactivity reached the brain via the nerve pathways and how much via the blood.

Intravenous, subcutaneous, intramuscular: injection and depot

Intravenous administration skips absorption altogether: the compound is in the blood completely and at once. That is why this route is the reference against which the bioavailability of all other routes is measured ^[1].

A subcutaneous injection, by contrast, creates a depot in the tissue under the skin. From there the compound first has to move through the connective tissue and then cross into blood capillaries or lymphatic vessels. Some of it may already be broken down at the injection site, a kind of local first pass. Which path dominates depends on factors such as charge and molecular size ^[9]. In an experiment in sheep, the fraction absorbed via the lymph rose linearly with molecular weight; molecules above about 16,000 daltons were absorbed mainly via the lymphatics ^[10]. The study, however, covered only four substances with three animals each.

Because swallowed peptides are degraded in the digestive tract and barely absorbed ^[2], peptide and protein drugs such as insulins or antibodies are often injected under the skin ^[9]. For peptides such as BPC-157 or TB-500, too, subcutaneous injection is the common route online according to the library profiles, although its pharmacokinetics have not been studied in humans.

An injection does not guarantee complete uptake, though. For the peptide BPC-157, absolute bioavailability after intramuscular injection was about 14–19% in rats and 45–51% in beagle dogs; the half-life of the unchanged peptide was under 30 minutes in both species ^[11]. These figures show two things: even from muscle, part of the dose does not reach the circulation unchanged, and the values differ considerably between species. How to translate such animal data to humans is considered an unsolved problem for subcutaneously administered biologics; suitable mechanistic models are lacking ^[9].

Transdermal: the 500-dalton limit

Skin is first and foremost a barrier. Its main defence is the horny layer (stratum corneum), the outermost layer of the skin. According to the widely cited “500 dalton rule”, a molecule must weigh less than 500 daltons to be absorbed through the skin ^[12]. The authors argue this partly on the grounds that virtually all known contact allergens, the commonly used topical drugs and all transdermal patch drugs known at the time fall below this limit ^[12]. It is therefore a rule of thumb derived from observation, not a law of nature.

For peptides it is still revealing. Even the heptapeptide Semax, at about 814 daltons (calculated from its amino acid sequence), is well above it. By this rule, meaningful uptake of intact peptides through intact skin would not be expected.

Inhalation

Via the lungs, small molecules can be delivered with very rapid onset, little metabolism and high bioavailability. Large molecules can also enter the body this way without an injection, as the then-new approval of a first inhaled insulin demonstrated. Apart from anaesthetic gases, however, medicine was slow to use this route for whole-body effects. How well an inhaled compound arrives depends strongly on lung physiology and on the composition of the formulation ^[13].

Rectal: partly bypassing the liver

Suppositories are an alternative when swallowing is not possible, for example during nausea and vomiting, seizures or before surgery. The rate and extent of absorption are often lower than with oral dosing, possibly because of the small absorptive surface, and depend strongly on the formulation. For some drugs, however, such as morphine, lidocaine or propranolol, more was absorbed rectally than orally. This is interpreted as partial avoidance of hepatic first-pass metabolism; for lidocaine, the extent depended on where in the rectum the drug was released. Irritation of the mucosa has also been described, and with long-term use of some drugs even ulceration ^[14].

The blood-brain barrier: in the blood is not in the brain

For nootropics, bioavailability is only half the answer. A substance can reach the blood in full and still barely reach the brain. The blood-brain barrier is formed by the endothelium of the brain capillaries ^[15] and essentially lets only small, non-polar substances through ^[6].

How strict it is was summed up in a widely cited estimate by the US researcher William Pardridge: the barrier keeps nearly 100% of large molecules and more than 98% of all small-molecule drugs out of the brain ^[15]. The figure comes from a review and should be read as an order of magnitude, not an exact measurement. For peptides, then, the barrier is a second and often even higher hurdle after they reach the blood. That is precisely why the nasal route attracts so much research interest ^[6].

Even for small substances the body makes itself, crossing is not a given: for creatine, brain levels rise measurably according to the library profile, but only to a limited extent and mostly over weeks. For many other profiles, the entry on the route into the brain simply reads “not studied” or “not verified”.

What this means for supplements and peptides

Three questions help in judging a claimed effect: does the substance reach the blood by this route? How much of it arrives unchanged? And does it reach the place where it is supposed to act? The profiles in the nootropics library (in German) summarise what is known. Some examples:

• Curcumin: oral bioavailability is estimated at under 1%, and free curcumin is mostly undetectable in blood. Many formulations raise measurable levels many times over; some of the studies on them were funded by the manufacturer.
• Caffeine: the counterexample. It is absorbed rapidly and completely from the gut, without a notable first-pass effect. Oral does not automatically mean poor.
• Zinc: how well it is absorbed depends on the compound. In one study, about 61% was absorbed from citrate and gluconate in the fasting state, and about 50% from oxide. Lozenges are a buccal form; after zinc gel in the nose, a case series of people losing their sense of smell has been described. The nasal route carries risks, too.
• Semax: in studies, it is given into the nose. Brain uptake has only been measured in rats, and its half-life in humans has not been studied.
• BPC-157: online, it is mostly injected under the skin, yet this very route has not been characterised pharmacokinetically in any study. Oral bioavailability has not been measured in any species.
• CJC-1295: with its so-called DAC group, it binds to albumin in the blood, extending the half-life after subcutaneous dosing to 5.8–8.1 days.
• NMN: in randomised trials, NAD+ in the blood rises. In mice, however, orally administered NMN was largely broken down to nicotinamide in the liver, whereas after intravenous dosing it was distributed intact.

Without such data, a claimed effect is hard to assess: an effect in the lab, or after an injection in an animal study, says nothing about whether enough of the compound reaches the target tissue by the advertised route. This page deliberately gives no doses or intake recommendations. Anyone considering a product should discuss it with a doctor.