The Interplay Between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol Oral Formulations

Franco, Valentina; Gershkovich, Pavel; Perucca, Emilio; Bialer, Meir

doi:10.1007/s40262-020-00931-w

Cited by 38 publications

(32 citation statements)

References 50 publications

(92 reference statements)

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“…Cytochrome P450 is a major enzyme family involved in hepatic microsomal drug metabolism, of which CYP3A is the most important, involved in approximately 45%‐60% of prescribed drugs. Experimental results from in vitro and animal studies strongly suggest that thyroid hormones reduce CYP3A activity in humans and may influence the pharmacokinetics of concomitant CYP3A substrate drugs 16‐18 …”

Section: Discussionmentioning

confidence: 99%

“…In our cohort, two patients on levothyroxine showed a fourfold increase in CBD AUC 0–6 as compared to the other patients without the thyroid hormone. This observation may be explained by the strong inhibition that levothyroxine exerts on cytochrome P450 (especially CYP3A4) increasing the exposure of numerous drugs subjected to metabolism mediated by these enzymes 14, 16‐18 . Moreover, two patients had an NGT for feeding purposes, and they showed a significant decrease in CBD exposure.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

et al. 2020

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Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil‐based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3‐19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9‐6.2), 49.6 ng/mL (14.4‐302.0), and 226.3 ng ⋅ h/mL (70.5‐861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine‐CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

et al. 2020

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“…Re-directing drug transport from the intestine through the intestinal lymphatic system, rather than the portal blood, provides a means to improve the oral bioavailability of drugs that have high hepatic first-pass metabolism ( Trevaskis et al, 2008 ; Yanez et al, 2011 ; Bala et al, 2016 ; Hu et al, 2016 ; Franco et al, 2020 ). In contrast to the mesenteric venous network that collects the blood from the intestine into the portal vein before passing through the liver, the intestinal lymphatics drain into the thoracic duct and empty directly into the systemic blood via the major veins in the neck.…”

Section: Introductionmentioning

confidence: 99%

Triglyceride-Mimetic Prodrugs of Buprenorphine Enhance Oral Bioavailability via Promotion of Lymphatic Transport

Quach

Han

et al. 2022

Front. Pharmacol.

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Buprenorphine (BUP) is a potent opioid analgesic that is widely used for severe pain management and opioid replacement therapy. The oral bioavailability of BUP, however, is significantly limited by first-pass metabolism. Previous studies have shown that triglyceride (TG) mimetic prodrugs of the steroid hormone testosterone circumvent first-pass metabolism by directing drug transport through the intestinal lymphatics, bypassing the liver. The current study expanded this prodrug strategy to BUP. Here different self-immolative (SI) linkers were evaluated to conjugate BUP to the 2 position of the TG backbone via the phenol group on BUP. The SI linkers were designed to promote drug release in plasma. Lipolysis of the prodrug in the intestinal tract was examined via incubation with simulated intestinal fluid (SIF), and potential for parent drug liberation in the systemic circulation was evaluated via incubation in rat plasma. Lymphatic transport and bioavailability studies were subsequently conducted in mesenteric lymph duct or carotid artery-cannulated rats, respectively. TG prodrug derivatives were efficiently transported into the lymphatics (up to 45% of the dose in anaesthetised rats, vs. less than 0.1% for BUP). Incorporation of the SI linkers facilitated BUP release from the prodrugs in the plasma and in concert with high lymphatic transport led to a marked enhancement in oral bioavailability (up to 22-fold) compared to BUP alone. These data suggest the potential to develop an orally bioavailable BUP product which may have advantages with respect to patient preference when compared to current sublingual, transdermal patch or parenteral formulations.

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“…Indeed, the fatty acids generated by the lipolysis of medium and long chain triglycerides undergo several different processes: long chain fatty acids are associated to chylomicrons that are secreted into the lymphatic system instead of the portal vein. Thus, THC and CBD, used in combination with LCT, can bypass the liver, decreasing potential pre-systemic metabolism [ 41 ]. By avoiding loss in pre-systemic metabolism in the liver, cannabinoids can reach 22% bioavailability [ 84 ].…”

Section: Pharmaceutical-grade Cannabinoid Formulationsmentioning

confidence: 99%

Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain

Stella

Baratta

Pepa

et al. 2021

Drugs

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The field of Cannabis sativa L. research for medical purposes has been rapidly advancing in recent decades and a growing body of evidence suggests that phytocannabinoids are beneficial for a range of conditions. At the same time impressing development has been observed for formulations and delivery systems expanding the potential use of cannabinoids as an effective medical therapy. The objective of this review is to present the most recent results from pharmaceutical companies and research groups investigating methods to improve cannabinoid bioavailability and to clearly establish its therapeutic efficacy, dose ranges, safety and also improve the patient compliance. Particular focus is the application of cannabinoids in pain treatment, describing the principal cannabinoids employed, the most promising delivery systems for each administration routes and updating the clinical evaluations. To offer the reader a wider view, this review discusses the formulation starting from galenic preparation up to nanotechnology approaches, showing advantages, limits, requirements needed. Furthermore, the most recent clinical data and meta-analysis for cannabinoids used in different pain management are summarized, evaluating their real effectiveness, in order also to spare opioids and improve patients’ quality of life. Promising evidence for pain treatments and for other important pathologies are also reviewed as likely future directions for cannabinoids formulations.

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The Interplay Between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol Oral Formulations

Cited by 38 publications

References 50 publications

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

Triglyceride-Mimetic Prodrugs of Buprenorphine Enhance Oral Bioavailability via Promotion of Lymphatic Transport

Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain

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