Bioavailability Enhancement By Attenuating Presystemic Metabolism

In regards to oral bioavailability, much research and discussion have been levied against two issues: solubility and permeability. Depending on the drug molecule, its dose, and its application, release from the oral dosage form, dissolution into gastrointestinal fluids, and avoidance of precipitation may each require significant formulation efforts and strategies. Permeability is also a considerable problem for highly hydrophilic or highly hydrophobic molecules (i.e. logP values <1.5 or >5). To handle these issues better, several systems have been devised to guide drug developers. The first common one was Lipinski’s “Rule of 5”,¹ followed by Amidon’s “Biopharmaceutical Classification System” (widely known as BCS),² Benet’s “Biopharmaceutical Biopharmaceutics Drug Disposition Classification System” (BDDCS),³ and most recently a “refined Developability Classification System” (rDCS).⁴ Although these frameworks vary in purposes and methods, their common theme is to understand the limiting factors determining oral drug bioavailability.

Overall, absolute oral bioavailability (F_po) may be estimated by multiplying the fraction absorbed (F_a), the intestinal availability (F_g), and the hepatic availability (F_h), as shown in Equation 1 below. For many pharmaceuticals, considerations of solubility and permeability (determinants of F_a) may suffice for bioavailability estimations and comparisons, if F_g and F_h are close to 1. However, on their way to systemic blood circulation, some drugs are extensively metabolized in the intestine and the liver. This presystemic metabolism can deliver a “one, two punch” resulting in low and variable oral absolute bioavailability. Thus, oral bioavailability could be maximized by improving F_a, F_g, and F_h.

Equation 1: F_po = F_a*F_g*F_h

One common approach to overcoming rapid presystemic metabolism is through structural modification of the active compound. Functional groups susceptible to metabolism (such as phenols) could be concealed through ester formation, as in some prodrug approaches. The structure of the molecule could also be redesigned to avoid the susceptible group followed by additional activity testing. However, both of these approaches require the generation of new molecules and would necessitate expensive toxicology testing in addition to clinical studies. The advantage of our patented approach⁵ is that with a relatively small amount of preclinical and formulation work, the approach can be tested clinically.

This article will discuss the approach as applied to three different types of compounds.

Application 1: Buprenorphine

Several buprenorphine products are marketed in the US to treat the epidemic of opioid use disorder, including sublingual or buccal products, and a monthly depot injectable formulation. However, there has been no orally swallowed formulation of buprenorphine itself. Recently, an ester prodrug of buprenorphine (buprenorphine hemiadipate) was under development for oral dosing, but failed in Phase 1 clinical trials.⁶ Buprenorphine itself has very low oral bioavailability^7,8 despite good solubility and permeability.⁸ Buprenorphine has a high intrinsic hepatic clearance suggesting a high hepatic extraction ratio, thus a low hepatic availability (F_h), which we estimated to be 0.29.^8,9 Additionally, the intestinal metabolism of buprenorphine is also extensive, resulting in a low intestinal availability (F_g), which we estimated as 0.04.^8,9 Even granting a fraction absorbed (F_a) of 1, the absolute oral bioavailability of buprenorphine in humans is estimated between 1 and 3%.^8-10 Therefore, the very low F_g is the major factor causing low F_po of buprenorphine. Meanwhile, high oral doses of buprenorphine would not feasibly overcome its low oral bioavailability due to the high cost of pharmaceutical grade buprenorphine (~$800/g).

Thus, both intestinal and hepatic presystemic metabolism are problems to be overcome in attempts to formulate an orally swallowed buprenorphine product. However, buprenorphine metabolism is complex, involving both oxidation by CYP isoforms 3A4, 2C8, and 2D6, and glucuronidation by UGT isoforms 1A1, 2B7, and 1A3.^8,9,11,12 So overcoming these multiple metabolic barriers presents quite a challenge. To address this challenge, we screened many substances which have GRAS or dietary supplement status for their abilities to inhibit the oxidation and/or glucuronidation of buprenorphine in pooled human intestinal or hepatic microsomes.⁸ We also considered their dosing ranges and likely BCS class assignments, and further investigated their efficacies and potencies for both routes of metabolism in both organs. The results led us to a short list of compounds that would have the greatest in vivo potential, including pterostilbene, α-mangostin, chrysin, silybin, and ginger extract. From further studies, we calculated that doses of pterostilbene in the range of 20-25mg would boost buprenorphine Fpo to about 80%, although we also estimated an increase in variability in AUC. We then performed simulations and extrapolations, predicting that a dose of ~2mg of pterostilbene is expected to boost the oral bioavailability of buprenorphine to approximately 35%, on par with a sublingual product, meanwhile minimizing variability.¹⁰ We look forward to the opportunity to perform clinical testing on prototypes containing combinations of pterostilbene and other GRAS or dietary compounds.

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Application 2: Phenylephrine

In the United States, the Combat Methamphetamine Epidemic Act of 2005 has made access to pseudoephedrine-containing decongestants more difficult, and many products replacing pseudoephedrine with phenylephrine have been marketed. Meanwhile, the efficacy of phenylephrine has been doubted.^13,14 The absolute oral bioavailability of phenylephrine is commonly listed as 38±14%, based upon a study with only three subjects in the oral dosing phase.¹⁵ Although widely quoted,^16-18 the lack of scientific rigor and reproducibility in this study is obvious. We hypothesize that the absolute oral bioavailability of phenylephrine may be much lower, and that this low and variable bioavailability may be one significant reason for its questionable clinical efficacy.

With phenylephrine being an OTC drug, many drug products are mar- keted, but an opportunity may exist for a more reliable phenylephrine product. Our data have shown that combinations of certain GRAS and dietary compounds can inhibit the main routes of phenylephrine pre- systemic metabolism, namely sulfation and oxidation.^5,19 Specifically, these data show that certain combinations of GRAS and dietary com- pounds (such as resveratrol, zingerone, quercetin, and vanillin) can strongly inhibit phenylephrine presystemic metabolism.

Opportunities and Challenges

Besides the applications for the drugs discussed above, the same approach could be applied to other compounds with extensive phase 1 or phase 2 presystemic metabolism. These could include other opioids and other adrenergics, as well as estrogen-related compounds such as 2-methoxyestradiol and raloxifene. Additionally, the approach could potentially be adapted to compounds with high efflux transport by P-glycoprotein and the Breast Cancer Resistance Pump. Variability is another issue to be overcome; for example, morphine sulfate oral bioavailability is well-known to be variable, and new formulations solving this problem could be produced.

Another opportunity is in the area of nutraceuticals. Many natural products are also quickly metabolized presystemically resulting low oral bioavailability, as is the case with buprenorphine and phenylephrine. The dietary supplement market in the US is estimated to grow from $31.7B in 2016 to $56.7B in 2024.²⁰ The abundance of natural products and interest in tapping this market has resulted in numerous preclinical studies for potential treatments of common diseases such as diabetes, obesity, dyslipidemia, hypertension, cancers, and even longevity. Unfortunately, many clinical studies have been performed on various pure natural compounds or herbal extracts have failed to show encouraging results. However, many of these studies have failed to consider the biopharmaceutical and pharmacokinetic issues associated with the natural products being tested, thus contributing to clinical failures. Those planning clinical studies would do well to reverse that trend.

Meanwhile being lured by the hopes of promising in vitro and preclinical activities but recognizing potential bioavailability issues, several complex and costly strategies have been attempted such as prodrug approaches and nanoparticle formulations, as with curcumin.^21,22 However,unlessprescriptiondrugstatuscanbeobtained for these products, their high costs may limit their marketability. We have applied our approach using in vitro studies, demonstrating its feasibility with several phenolic natural molecules (unpublished data). Although further studies are needed to refine the approach for individual applications, we anticipate this approach would result in cost-effective clinically reproducible dietary supplements.

In the case of the KALETRA® (lopinavir/ritonavir) and STRIBILD® (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) products, CYP3A inhibitors (ritonavir and cobicistat, respectively) are included in the formulation and are known to have systemic effects on drug metabolism, as indicated in their prescribing information. As a result, patients and healthcare providers using these medications need to be especially vigilant in avoiding drug-drug interactions. By inhibiting presystemic metabolism using strategically minimal doses of GRAS or dietary compounds which are themselves quickly eliminated presystemically, unwanted systemic drug-drug interactions could be avoided clinically by separating dosing times. In the case of some dietary compounds, it may be challenging to obtain excipient-grade material for inclusion in the finished products.

Meanwhile, clinical studies have shown mixed results in the use of dietary compounds for bioavailability enhancement. For example, piperine (from black pepper) inhibits human P-glycoprotein and CYP3A4,²³ and enhances the oral bioavailability of theophylline and propranolol as demonstrated in humans.²⁴ In animal models, piperine increases the oral bioavailability of curcumin, resveratrol, epigallocatechin gallate, and amoxicillin.^25-28 Additionally, curcumin has also been shown to inhibit numerous enzymes involved in presystemic elimination.²⁹ However, in a clinical study with healthy volunteers, piperine and curcumin at fairly high doses failed to change the AUC values for acetaminophen, midazolam, or flurbiprofen, but modestly increased Cmax for acetaminophen.³⁰ As noted in the study, circulating plasma concentrations of uncon- jugated piperine or curcumin were undetectable (<0.6μM or < 0.05μM, respectively) despite the high doses, but conjugated metabolites were abundant. Therefore, to make an oral bioavailability enhancement strategy clinically successful, one would need to pay careful attention to the biopharmaceutics and disposition of the enhancers as well as the active compounds. Particularly, it would be best to maximize the exposure of the intestinal and hepatic enzymes to the enzyme inhibitors during the absorption phase of the active ingredient.

Conclusion

Despite the wealth of available literature regarding solubility and permeability enhancement approaches, relatively little is established regarding bioavailability enhancement by inhibition of presystemic metabolism. Our patented approach works to address the issues discussed above by using combinations of enzyme inhibitors directed toward multiple metabolic pathways.⁵ This approach would be well-suited for compounds with rapid intestinal and/or hepatic metabolism resulting in low and variable oral bioavailability, especially for older drug molecules like buprenorphine and phenylephrine and nutraceutical compounds. Hopefully, more partnerships between industry and academia will help to bring many new products to market.

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About the Author:

Phillip M. Gerk received his Doctor of Pharmacy (Pharm.D.) degree at the University of Illinois at Chicago, then did a clinical research fellowship at Auburn University. He then attended the University of Kentucky where he received his Ph.D. and stayed to perform postdoctoral research. He has been a faculty member at Virginia Commonwealth University in the Department of Pharmaceutics since 2004, where he performs his research on drug metabolism, transport, and oral bioavailability.