Different impacts of intestinal lymphatic transport on the oral bioavailability of structurally similar synthetic lipophilic cannabinoids: Dexanabinol and PRS-211,220

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Abstract

The aim of this article was to investigate the role of intestinal lymphatic transport in the oral bioavailability of two structurally similar synthetic lipophilic cannabinoids: dexanabinol and PRS-211,220. For this purpose, the long chain triglyceride (LCT) solubility and affinity to chylomicrons ex vivo of both cannabinoids were evaluated. Their oral bioavailability was assessed in rats following administration in a lipid-free and a LCT-based formulation. The intestinal lymphatic transport of these two molecules was also directly measured in a freely moving rat model. LCT solubility of dexanabinol and PRS-211,220 was 7.9 ± 0.2 and 95.8 ± 5.3 mg/g, respectively. The uptake by chylomicrons was moderate (31.6 ± 5.2%) and high (66.1 ± 2.4%), respectively. The bioavailability of dexanabinol (37%) was not affected by LCT solution, whereas administration of PRS-211,220 in LCT improved the absolute oral bioavailability three-fold (from 13 to 35%) in comparison to the lipid-free formulation. The intestinal lymphatic transport of dexanabinol and PRS-211,220 was 7.5 ± 0.8 and 60.7 ± 6.8% of the absorbed dose, respectively. In conclusion, despite structural similarity and similar lipophilicity, dexanabinol and PRS-211,220 exhibited a very diverse pattern of oral absorption, and the lymphatic system played quite a different role in the oral bioavailability of these molecules. The low lymphatic transport of dexanabinol is likely driven by relatively lower affinity to chylomicrons and lower LCT solubility.

Introduction

The oral route is the most convenient method of drug administration for both the patient and medical care professionals. Following oral administration, most drugs are absorbed directly into portal blood, but lipophilic molecules can be also transported to the systemic circulation by the intestinal lymphatic system (Charman and Porter, 1996, Edwards et al., 2001). Intestinal lymphatic transport is a complex process consisting of several consecutive events in intestinal lumen and enterocyte. The key mechanism of the intestinal lymphatic transfer is the association of the lipophilic drug with chylomicrons (CM) in the enterocyte and subsequent uptake of these drug-containing large lipoproteins by the intestinal lymphatic system (Charman and Stella, 1986, Porter and Charman, 2001, O’Driscoll, 2002). The degree of association with CM was previously proposed by our group to be indicative of the intestinal lymphatic transport potential of lipohilic drugs (Gershkovich and Hoffman, 2005). The physicochemical properties of molecules required for lymphatic transport of drugs are thought to be high lipophilicity (log P > 5) and reasonable solubility in long chain triglycerides (LCT) (Charman and Stella, 1986, Charman, 2000). However, high log P value and high LCT solubility does not always lead to significant intestinal lymphatic transport (Myers and Stella, 1992, Hauss et al., 1994, Grove et al., 2006).

Although lymphatic transport and association with CM and other triglyceride-rich lipoproteins may lead to many pharmacokinetic and pharmacodynamic consequences (Eder, 1982, Gupta and Benet, 1990, Humberstone et al., 1998a, Humberstone et al., 1998b, Wasan and Cassidy, 1998, Wasan et al., 2002, Wasan et al., 2006, McIntosh et al., 2004, Shayeganpour et al., 2005, Brocks et al., 2006, Gershkovich et al., 2007), the foremost reason for the broad interest in lymphatic transport is the potential to utilize this pathway to increase the oral bioavailability of highly lipophilic drugs. Lymphatic transport may contribute to the increase in the oral bioavailability of lipophilic compounds by a number of potential mechanisms: additional pathway of transfer of lipophilic compound from the enterocyte to the blood (Dahan and Hoffman, 2005), bypass of hepatic first-pass metabolism (Charman and Porter, 1996) and reduction in intestinal first-pass metabolism (Trevaskis et al., 2006a). However, there is scarce knowledge regarding the impact of lymphatic transport on bioavailability, since the number of compounds for which lymphatic transport is quantified is very limited due to the complicated surgical procedures required. The most extensive research in this area has been performed on halofantrine, a highly lipophilic drug. It was found that intestinal lymphatic transport accounted for a very high portion of the total oral bioavailability of this compound in rat (Porter et al., 1996, Caliph et al., 2000) and even more in dog (Khoo et al., 2001, Khoo et al., 2003, Holm et al., 2003).

The aim of the current work was to assess the ability of the intestinal lymphatic transport to improve the oral bioavailability of two structurally similar synthetic cannabinoids, dexanabinol and PRS-211,220 (Fig. 1). Despite very encouraging pharmacological properties (Mattes et al., 1993), cannabinoids are barely used in clinical practice, primary due to their low bioavailability following oral administration. The low oral bioavailability of natural and synthetic cannabinoids is explained mainly by their high lipophilicity and extensive hepatic first pass metabolism (Agurell et al., 1986, Mattes et al., 1993, Bland et al., 2005). Dexanabinol (HU-211) is a synthetic cannabinoid analogue which acts as a non-competitive N-methyl d-aspartate (NMDA) receptor antagonist and antioxidant. This compound was shown to be highly neuroprotective in an animal model of brain injury (Shohami et al., 1995), but recently completed phase III clinical trials have shown less promising results (Maas et al., 2006). PRS-211,220 is another synthetic cannabinoid with high neuroprotective potential as demonstrated in a mid-cerebral artery occlusion rat model (Lavie et al., 2002). These two compounds have similar structure and similar calculated octanol/water partition (i.e. clog P) values, but quite different solubility in LCT and affinity to CM.

The experimental design that was used in this work entailed two stages:

  • 1.

    Assessments of bioavailability of two lipophilic cannabinoids following their oral administration to rats in lipid-free and LCT-based formulations, as LCT have been shown to facilitate intestinal lymphatic transport of lipophilic drugs (O’Driscoll, 2002).

  • 2.

    Quantification of intestinal lymphatic versus portal transport of the synthetic cannabinoids in a freely moving rat model following their administration in LCT-based formulation and direct measurement of the tested drug concentrations in lymph fluid and plasma concurrently.

Section snippets

Materials

Dexanabinol and PRS-211,220 were kindly provided by Pharmos Ltd. (Rehovot, Israel). All other chemicals were of analytical reagent grade, and solvents were of HPLC grade.

Calculation of physicochemical properties

The physicochemical properties of the tested compounds were calculated by ACD/Lab version 10.0 (Advanced Chemistry Development Inc., Toronto, Canada).

Solubility of the tested compounds in long chain triglycerides

Excess amounts of tested compounds were added to peanut oil. Following incubation for 72 h at 37 °C with constant mixing using magnetic stirrer, samples were centrifuged at 1050 × g

Physicochemical properties of tested compounds

The physicochemical properties of dexanabinol and PRS-211,220, including the experimental solubility in LCT and affinity to CM are summarized in Table 1. Interestingly, despite very similar clog P values, PRS-211,220 has shown significantly higher experimental solubility in LCT and significantly lower calculated water solubility than dexanabinol. For both compounds the calculated log P was identical to the corresponding log D(7.4) value, indicating that neither dexanabinol nor PRS-211,220 are

Discussion

While the number of highly lipophilic compounds under biopharmaceutical development is constantly increasing (Lipinski et al., 2001), these molecules frequently have poor and erratic oral absorption and consequently are not selected to be leading compounds despite their promising pharmacological properties. There are a few techniques to improve the oral bioavailability of lipophilic compounds, including optimization of intestinal dissolution profile by choosing a proper lipid-based formulation,

Conclusion

It was demonstrated that despite structural similarity and similar lipophilicity, dexanabinol and PRS-211,220 exhibit a very diverse pattern of oral absorption, and the lymphatic system played quite a different role in the oral bioavailability of these molecules. Dexanabinol, which has moderate affinity to chylomicrons, low solubility in LCT and relatively high predicted solubility in water, shows relatively good oral bioavailability when administered in lipid-free formulation, and intestinal

Acknowledgments

This paper is a part of Pavel Gershkovich's PhD dissertation. This study was supported by Israeli Consortium of Pharmalogica. We would like to thank Hava Kleiman, Constantin Itin and Joseph Fanous for excellent technical assistance and Dr. Josh Backon for constructive comments. Prof. Amnon Hoffman is affiliated with the David R. Bloom Center for Pharmacy at The Hebrew University of Jerusalem.

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