Introduction: The most commonly used immunosuppressive drugs (ISDs) which can prevent rejection of transplanted organs include cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus and everolimus. The clinical efficacy of these drugs is greatly influenced by their in vivo performance. Various pharmacokinetic and toxicological constraints limit their therapeutic activity which is a matter of serious concern.
Areas covered: An extensive review establishes that poor solubility in intestinal milieu; substantial gut metabolism by CYP3A along with simultaneous efflux by P-glycoprotein and significant hepatic first-pass metabolism are all potential hindrances resulting in poor oral absorption of highly lipophilic ISDs. On top of that, toxicities accompanied by ISDs further affect their overall therapeutic efficacy.
Expert opinion: This review discusses various barriers to the efficient absorption of ISDs and the potential formulation strategies for resolving such ambiguities. The article highlights the potential role of lymphatic targeting by means of novel lipid nanocarriers in modifying systemic availability, toxicity and efficacy profiles of ISDs. Finally, the present manuscript discusses that integration of P-glycoprotein and CYP inhibitors in lipid nanocarrier system provides a novel perspective of overcoming the significant barriers that leads to poor bioavailability of ISDs.
Keywords: CYP3A; P-glycoprotein efflux; bioavailability; immunosuppressive drugs; in vivo performance; lipid nanocarriers.