When Good Absorption Doesn’t Matter

Good intestinal absorption is looked upon with favor by both researchers and clinicians. Often, it predicts lower, more affordable dosing and improved efficacy. But absorption is not always a relevant matter. There are 3 situations in which good absorption is less important:

The affinity for the molecular target is high. A stronger interaction with the target (nanomolar IC50 or below) means that a lower intracellular concentration is required for efficacy. For example, the strong (nanomolar) potency of the hemp oil terpene beta-caryophyllene at the cannabinoid CB2 receptor suggests that low bioavailability (or a low dose) is permissible. In contrast, the weaker (micromolar) potency of flavonoids at GABA receptors means that higher bioavailability (or a high dose) is required for clinical efficacy.
The primary mechanism is modification of the microbiome. Many antibiotic drugs are absorbed, distributed, and circulated back to the gut, but topical modes of action in the intestine also occur. Membrane permeation is required to enter bacterial cells, but these bugs are quite charitable to enormous, polar compounds that fail to enter the host’s gut wall, including many natural agents whose microbiome-modifying actions have gone unrecognized until recently. Examples include curcumin and berberine, which exert immunologic and metabolic health benefits, in part, through modification of the microbiome.
The compound is a precursor to an active microbial metabolite (postbiotic). Bacterial enzymes enjoy dismantling complex natural compounds from plants and reducing their size and polarity, rendering metabolites with vastly enhanced pharmacokinetic properties. For example, dietary fiber and ellagitannins are not absorbed in the mammalian gut, but commensal bacteria convert them to small, systemically available derivatives. Fiber is converted to short chain fatty acids such as butyrate, and ellagitannins are converted to urolithins, both of which have excellent absorption properties and reach clinically effective levels plasma and tissues.