A Pharmacokinetic Study of Mix-160 by LC-MS/MS: Oral Bioavailability of a Dosage Form of Citroflavonoids Mixture

This study was performed to evaluate and compare the pharmacokinetic parameters between two dosage formulations of hesperidin and naringenin: mixture and tablet. Our objective was to determine that the flavonoid tablet does not significantly modify the pharmacokinetic parameters compared with the mixture. For this study, we administered 161 mg/kg of either mixture (Mix-160) or tablet composed of hesperidin and by intragastric administration. Blood microsamples were collected from tail vein up to 24 h. Serum flavonoid extraction was performed by solid phase extraction and analyzed by LC-MS/MS of triple quadrupole (QqQ). Serum concentration vs. time plot showed that data fitted for a first-order model. The pharmacokinetic parameters were calculated by a noncompartmental model. The results showed that the absorption constant is higher than the elimination constant. The first concentration was found at five minutes, and minimal concentration at 24 h after administration, suggesting a enterohepatic recirculation phenomena and regulation of liver cytochromes’ activity. We did not find meaningful differences between the pharmacokinetic parameters of both samples. We concluded that tablet form did not interfere with the bioavailability of hesperidin and naringenin, and it could be a suitable candidate for developing a drug product.

Synergistic effect of myricetin and phenolic acid derivatives on reversal of dengue fever related thrombocytopenia and its pharmacokinetics study in Plasma by using HPLC and UPLC-Q-TOF

Background: Carica papaya L. is consumed worldwide because of its high nutritional and medicinal benefits due to the presence of polyphenols. Objective: The present study was undertaken to investigate the effects of polyphenols present in C. papaya in dengue fever against cyclophosphamide (CP) induced thrombocytopenia in balb/c mice. Method: Platelet count (PC), total leukocyte count (TLC), activated partial thromboplastin time (aPTT), prothrombin time (PT), anti-platelet antibodies IgG and IgM were analysed in blood/serum of animals treated for 21 days with standardized C. papaya leaf juice (CPLJ) and its bioactivity guided selected fractions (SFs). A new HPLC-PDA method was developed to study pharmacokinetic (PK) profile of phytoconstituents in plasma of bioactive butanol fraction (BBF) and CPLJ treated mice. CPLJ and BBF were metabolically distinguished by UPLC-qTOF/MS for metabolite signature. Results: Animals orally treated with BBF elicited significant reduction in blood/serum levels of aPTT, PT, AST, ALT and antibodies IgG and IgM. However, thrombocyte count was significantly (p<0.01) increased. A total of 12 and 9 metabolites were tentatively identified using UPLC-qTOF/MS in BBF and CPLJ, respectively. PK parameters evaluated by noncompartmental model showed Cmax of plant flavonoids and phenolic acids including caffeic acid, para-coumaric acid, vanillic acid, myricetin and trans-ferulic acid (0.10, 0.49, 0.61, 5.97, 36.29 µg/mL, respectively) and half-life (24, 6, 26, 15 and 13 h), respectively. Conclusion: Collectively, our data suggest that the polyphenol enriched fraction of CPLJ might reverse acute thrombocytopenia by accelerating the platelets regeneration from megakaryocytes, providing strong rational for its use in the treatment of dengue fever-related thrombocytopenia. Thus, the BBF can be used as phytopharmaceuticals for the enhancement of platelets by using as adjuvants or alone.

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

These results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. The enantiomers of many chiral drugs not only exhibit different pharmacological effects in regard to targets that dictate therapeutic and toxic effects, but are also handled differently in the body due to pharmacokinetic effects. We investigated the pharmacokinetics of the enantiomers of N-acetyl-leucine after administration of the racemate (N-acetyl-DL-leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-leucine). Compounds were administered orally to mice. Plasma and tissue samples were collected at predetermined time points (0.25 to 8 h), quantified with liquid chromatography/mass spectrometry, and pharmacokinetic constants were calculated using a noncompartmental model. When administered as the racemate, both the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. When administered as the L-enantiomer, the dose proportionality was greater than unity compared to the racemate, suggesting saturable processes affecting uptake and/or metabolism. Elimination (ke and T1/2) was similar for both enantiomers. These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation. In brain and muscle, N-acetyl-L-leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-leucine and utilization by normal leucine metabolism. In summary, the enantiomers of N-acetyl-leucine exhibit large, unexpected differences in pharmacokinetics due to both unique handling and/or inhibition of uptake and metabolism of the L-enantiomer by the D-enantiomer. Taken together, these results have clinical implications supporting the use of N-acetyl-L-leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of isolated N-acetyl-L-leucine.

Effects of Xuesaitong on the Pharmacokinetics of Losartan: An In Vivo UPLC-MS/MS Study

The aim of this study was to examine whether Xuesaitong, a multiherbal formulation for coronary heart disease, alters the pharmacokinetics of losartan. Adult male Sprague Dawley rats randomly received losartan (10 mg/kg) or losartan plus Xuesaitong (10 mg/kg) through an oral gavage (n = 6). Multiple blood samples were obtained for up to 36 h to determine the concentrations of losartan and its active metabolite, EXP3174, through ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetics were estimated using a noncompartmental model. The half-life (t1/2) of losartan was decreased by Xuesaitong (4.26 ± 1.51 vs. 6.35 ± 2.10 h; P<0.05). The apparent volume of distribution (Vd) of losartan was also decreased by the combination of losartan and Xuesaitong (4.41 ± 1.61 vs. 7.20 ± 2.41 mL; P<0.05). The time to maximum concentration (Tmax) of losartan was increased by Xuesaitong (1.06 ± 1.04 vs. 0.13 ± 0.05 h; P<0.05). Xuesaitong also decreased the t1/2 of EXP3174 (8.22 ± 1.41 vs. 6.29 ± 1.38 h; P<0.05). These results suggest that there is a complex interaction between losartan and Xuesaitong. In addition to enhanced elimination of losartan and EXP3174, Xuesaitong may also decrease the absorption rate and Vd of losartan.

Effects of Berberine and Hwangryunhaedok-Tang on Oral Bioavailability and Pharmacokinetics of Ciprofloxacin in Rats

Hwangryunhaedok-Tang (HR) and berberine-containing single herbs are used to treat bacterial infection and inflammatory diseases in eastern Asia. The combination of berberine-containing herbal medicines and ciprofloxacin can be an excellent antibacterial chemotherapy against multidrug resistance bacteria. To evaluate the pretreatment effect of berberine and HR, vehicle, berberine (25 and 50 mg/kg/day), and HR (1.4 g/kg/day) were daily administered to rats for five consecutive days. On day 6, ciprofloxacin was administered (10 mg/kg, i.v. and 20 mg/kg, p.o.) to rats. To assess cotreatment effect of berberine and ciprofloxacin, berberine (50 mg/kg) and ciprofloxacin (20 mg/kg) were coadministered by single oral gavage. Pharmacokinetic data were estimated by noncompartmental model. Compared with ciprofloxacin alone (control group), coadministration of berberine (50 mg/kg) and ciprofloxacin significantly decreasedCmaxof ciprofloxacin (P<0.05). In addition, the pretreatment of berberine (50 mg/kg/day) and HR (1.4 g/kg/day) significantly decreasedCmaxandAUC0→∞, compared with control group (P<0.05). The oral bioavailability of ciprofloxacin was reduced by cotreatment of berberine and pretreatment of berberine and HR. Our results suggest that the expression of P-glycoprotein and organic anion and/or organic cation transporters (OAT/OCT) could take a role in reduced oral bioavailability of ciprofloxacin by berberine and HR.

Effect of Multiple Staggered Doses of Calcium on the Bioavailability of Ciprofloxacin

OBJECTIVE: To determine the effect on the relative bioavailability (Fr) of a staggered single dose of ciprofloxacin given two hours after a morning dose of calcium carbonate given three times daily over the three previous days. DESIGN: Thirteen male volunteers participated in this randomized, nonblinded, crossover investigation; 12 subjects were included in the final analysis. SETTING: Data collection and ciprofloxacin administration occurred at Albany Medical Center, a tertiary-care teaching institution. Calcium carbonate administration was on an outpatient basis. RESULTS: For 12 volunteers, the mean ± SD Fr of ciprofloxacin staggered with calcium was 0.87 ± 0.23 (noncompartmental model) and 0.98 ± 0.27 (compartmental model). Other statistically significant findings were a decrease in the time to maximum concentration of ciprofloxacin staggered with calcium in serum compared with ciprofloxacin alone (from 1.76 ± 0.54 to 1.23 ± 0.52 h in the noncompartmental model; p<0.05), and a decrease in the same parameter (from 1.92 ± 0.96 to 0.77 ± 0.53 in the compartmental model; p<0.005). Maximum concentration of ciprofloxacin staggered with calcium was decreased in the noncompartmental model compared with ciprofloxacin alone (from 2.11 ± 0.72 to 1.60 ± 0.33, respectively; p<0.05). The elimination half-life and area under the concentration-time curve of ciprofloxacin were not significantly altered. CONCLUSIONS: Repeated doses of calcium carbonate, administered two hours before ciprofloxacin, did not significantly alter the Fr of this fluoroquinolone.

Multiexponential, multicompartmental, and noncompartmental modeling. I. Methodological limitations and physiological interpretations

Multiexponential, multicompartmental, and noncompartmental analysis methods are conventional modeling tools in life science areas, and, on occasion, a number of facets of each are misunderstood, misused, or misinterpreted. We critically examine some of the assumptions, subtleties, and properties of each of these methodologies, with emphasis on their applicability and their interpretation in physiological terms. We discuss the similarities and differences in noncompartmental and compartmental approaches, their relationships with multiexponential models, and several important assumptions that must be satisfied in the practical application of these techniques. A key issue is the highly restricted structure of the noncompartmental model, limiting its applicability quite severely. Noncompartmental analysis is not model independent, as it is often called. Another issue is the importance and manner of choosing a suitable multicompartmental topology, consistent with system structure and modeling goals, when a physiological mapping of specific model parameters is desired.