## 2 Pharmacology of Piperine: In Vitro and In Vivo Studies
### Bioavailability-Enhancing Effect of Piperine  
Piperine increases the bioavailability of the coenzyme Q10 in plasma in a nonspecific fashion when orally administered [138]. The pharmacokinetics of ciprofloxacin changed when piperine was co-administered, emphasizing the fact that it acts as bioenhancer [139]. Similar results were reported for amoxicillin [140], rosuvastatin [141], omeprazole [142], magnolol [143], ampicillin and norfloxacin [144]. Piperine, as a bio enhancer, improves the systemic availability of oral propranolol and theophylline in healthy volunteers [145]. Similar results were obtained with carbamazepine, chlorzoxazone, fexofenadine, diclofenac, ackibuprofen [146], midazolam [147], resveratrol and nevirapine [148], vasicine and sparteine [149], as well as tamoxifen and endoxifen [150]. When piperine was combined with phenytoin, it increased its absorption, decreased the absorption half-life, and prolonged the elimination half-life (T\({}_{1/2}\)), and produced a higher area under the drug concentration curve (AUC) in comparison to phenytoin alone [151; 152; 153]. The new pharmacological preparation Risorine, composed of rifampicin, piperine and isoniazid, provides better results considering the cure rate [154] and more rifampicin in blood along with higher safety in comparison to standard antituberculosis therapy [155]. When orally administered with curcumin, it was found that piperine enhances its oral bioavailability in humans [156; 157], while when taken together with \(\beta\)-carotene, significantly greater increases in serum \(\beta\)-carotene occurred, pointing to the absorption-enhancing effect of piperine [158]. Also, piperine in the form of pro-nanolipospheres was found to be efficient in overcoming the limitations of variable and low oral bioavailability of cannabinoid's tetrahydrocannabinol and cannabidiol [159]. Piperine increases the bioavailability of emodin in rats [160], linarin [161], \(\beta\)-lactam antibiotics [162], fxofenadine [163], ginseng Rh2 [164], (-)-epigallocatechin-3-gallate [165], puerarin [166], oxyphenylbutazone [167] and diliazem [168]. In a study on human cancer cell line (monolayers of Caco-2 cells), [PERSON] et al. [169] found piperine to be an inhibitor of both human P-glycoprotein and CYP3A4, and that it also inhibited transport of the P-glycoprotein substrates digoxin and cyclosporine. Another study, performed on intestinal epithelial cells derived from a human ileoccal adenocarcinoma (HCT-8; ATCC No. CCL-244), found that piperine significantly increased the transepithelial electrical resistance of the cell monolayer [170]. At concentrations ranging from 50 and 100 \(\upmu\)M, prolonged co-incubation of Caco-2 cell monolayers with piperine increased P-gp activity through an up-regulation of cellular P-gp protein and MDR1 mRNA levels [171]. Co-administration of [172] increased docetaxel's pharmacokinetic activity on castration-resistant prostate cancer cells via inhibition of hepatic CYP3A4 activity, which resulted in an increased AUC, T\({}_{1/2}\) and maximum plasma concentration (C\({}_{\text{max}}\)) of docetaxel [172]. Piperine increases the C\({}_{\text{max}}\) and the elimination T\({}_{1/2}\) of domperidone in rats [173].