Many new chemical entities are discovered with high therapeutic potential, however, many of these compounds exhibit unfavorable pharmacokinetic properties due to poor solubility and/or poor membrane permeation characteristics. The latter is mainly due to the lipid-like barrier imposed by epithelial mucosal layers, which have to be crossed by drug molecules in order to exert a therapeutic effect. Another barrier is the pre-systemic metabolic degradation of drug molecules, mainly by cytochrome P450 enzymes located in the intestinal enterocytes and liver hepatocytes. Although the nasal, buccal and pulmonary routes of administration avoid the first-pass effect, they are still dependent on absorption of drug molecules across the mucosal surfaces to achieve systemic drug delivery. Bioenhancers (drug absorption enhancers of natural origin) have been identified that can increase the quantity of unchanged drug that appears in the systemic blood circulation by means of modulating membrane permeation and/or pre-systemic metabolism. The aim of this paper is to provide an overview of natural bioenhancers and their main mechanisms of action for the nasal, buccal, pulmonary and oral routes of drug administration. Poorly bioavailable drugs such as large, hydrophilic therapeutics are often administered by injections. Bioenhancers may potentially be used to benefit patients by making systemic delivery of these poorly bioavailable drugs possible via alternative routes of administration (i.e., oral, nasal, buccal or pulmonary routes of administration) and may also reduce dosages of small molecular drugs and thereby reduce treatment costs.

Arthropods have the capacity to evolve resistance to insecticides and insecticidal traits in genetically modified crops. Resistance development among Lepidoptera is a common phenomenon, and a repertoire of resistance mechanisms to various Cry toxins have been identified from laboratory, greenhouse, and field studies in this insect order. Elucidation of such resistance mechanisms is crucial for developing IRM (insect resistance management) strategies to ensure sustainable use of genetically modified crops. This mini review provides a comprehensive overview of mechanisms of resistance that have been reported for lepidopteran pests. This study demonstrated that resistance mechanisms are highly complex, and the most common mechanism of resistance is altered binding sites. It is yet to be established whether all these altered binding sites are regulated by an MAPK signaling pathway, which might suggest a universal mechanism of resistance in lepidopterans.

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