Acid diterpenes from Copaiba oleoresin (Copaifera langsdorffii): Chemical and plasma stability and intestinal permeability using Caco-2 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Copaiba oleoresin has been used in folk medicine in the treatment of bronchitis, syphilis, skin diseases and ulcers due to its anti-inflammatory and antiseptic activities, but there is no information about major compounds oral absorption to support the traditional use. AIM OF STUDY: Considering the potential of copalic (CA) and kaurenoic acid (KA) - major biological activity (in vitro) diterpenes found in the oleoresin, this study aimed to evaluate the intestinal permeability of CA and KA using Caco-2 cells model as predictive test for oral drug absorption. MATERIALS AND METHODS: Chemical stability at pH 1.2 and 7.4 and plasma stability were evaluated to mimic physiological conditions of the gastrointestinal tract. The intestinal permeability of CA and KA was evaluated in Caco-2 cells in the presence and absence of the P-glycoprotein inhibitor verapamil. RESULTS: CA and KA were rapidly degraded at pH 1.2 (0.2 M Clark-Lubs buffer). At pH 7.4 (0.1 M phosphate buffer), CA was stable for up to 24 h and KA for up to 6 h. In human plasma, CA and KA can be considered stable for 24 h and 12 h at 37 °C, respectively. Caco-2 cells were considered viable when incubated with CA or KA in the range of 3.9-250 µM for 24 h. CA and KA exhibited moderate apparent permeability (Papp) of 4.67 (±0.08) × 10-6 cm/s and 4.66 (±0.04) × 10-6 cm/s, respectively. Simultaneous incubation with verapamil showed that P-glycoprotein does not play a relevant role on CA and KA oral absorption, with Papp of 4.48 (±0.26) × 10-6 cm/s and 5.37 (±0.72) × 10-6 cm/s observed for CA and KA, respectively. CONCLUSION: The oral absorption of both CA and KA is driven by mainly passive permeability, is not limited by p-glycoprotein, but enteric-coated dosage forms should be used to avoid chemical instability in the gastric pH.

The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries.

PURPOSE: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). METHODS: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. CONCLUSION: SLCO1A2 -189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. TRIAL REGISTRATION: NCT 02399397 ( ClinicalTrials.gov ).