Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin.

The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0-4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP-1 and TNF-α, while the uncontrolled SLE group also showed higher plasma concentrations of IL-10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76-83.56) vs. 30.56 (22.69-41.15) ng⋅hour/mL) and its inactive metabolite ATV-lactone (98.74 (74.31-131.20) vs. 49.21 (34.89-69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30-457.00) vs. 654.5 (486.00-881.4) L/hour) and apparent volume of distribution (2,609 (1,607-4,234) vs. 7,159 (4,904-10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV-lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE.

Plasma mevalonic acid exposure as a pharmacodynamic biomarker of fluvastatin/atorvastatin in healthy volunteers.

Fluvastatin and atorvastatin are inhibitors of hydroxy-methylglutaryl-CoA (HMG-CoA) reductase, the enzyme that converts HMG-CoA to mevalonic acid (MVA). The present study reports for the first time the analysis of mevalonolactone (MVL) in plasma samples by UPLC-MS/MS as well as the use of MVA, analyzed as MVL, as a pharmacodynamics parameter of fluvastatin in multiple oral doses (20, 40 or 80 mg/day for 7 days) and atorvastatin in a single oral dose (20, 40 or 80 mg) in healthy female volunteers. this study presents the use of MVL exposure as a pharmacodynamics biomarker of fluvastatin in multiple oral doses (20, 40 or 80 mg/day for 7 days) or atorvastatin in a single oral dose (20, 40 or 80 mg) in healthy volunteers (n = 30). The administration of multiple doses of fluvastatin (n = 15) does not alter the values (geometric mean and 95 % CI) of AUC0-24 h of MVL [72.00 (57.49-90.18) vs 65.57 (51.73-83.12) ng∙h/mL], but reduces AUC0-6 h [15.33 (11.85-19.83) vs 8.15 (6.18-10.75) ng∙h/mL] by approximately 47 %, whereas single oral dose administration of atorvastatin (n = 15) reduces both AUC0-24 h [75.79 (65.10-88.24) vs 32.88 (27.05-39.96) ng∙h/mL] and AUC0-6 h [17.07 (13.87-21.01) vs 7.01 (5.99-8.22) ng∙h/mL] values by approximately 57 % and 59 %, respectively. In conclusion, the data show that the plasma exposure of MVL represents a reliable pharmacodynamic parameter for PK-PD (pharmacokinetic-pharmacodynamic) studies of fluvastatin in multiple doses and atorvastatin in a single dose.

Simultaneous analysis of the total plasma concentration of atorvastatin and its five metabolites and the unbound plasma concentration of atorvastatin: Application in a clinical pharmacokinetic study of single oral dose.

Atorvastatin (ATV) and its two active metabolites, o-hydroxy atorvastatin acid (o-OH-ATV) and p-hydroxy atorvastatin acid (p-OH-ATV) are responsible for its HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme-A) reductase inhibitory activity, while its corresponding inactive lactone forms (LAC) are related to the manifestation of myopathy. The present study reports the development and validation of a method for the simultaneous analysis of ATV and its five metabolites (o-OH-ATV, p-OH-ATV, ATV-LAC, o-OH-ATV-LAC, p-OH-ATV-LAC) as total plasma concentration and ATV as unbound plasma concentration using UPLC-MS/MS. The method was applied in a pharmacokinetic study following administration of a single oral 20, 40 or 80 mg ATV dose in healthy volunteers (n = 15). ATV and its five metabolites were separated on a C18 column using as mobile phase a mixture of 0.2% formic acid and acetonitrile (55:45, v/v) at a flow of 0.4 mL/min. The method showed linearity from 25 pg/mL to 200 ng/mL plasma as total concentration and from 6.25 pg to 25 ng/mL plasma ultrafiltrate as ATV unbound concentration. The coefficients of variation and the relative standard errors of the accuracy and precision analyses were <15%. The method allowed quantification of plasma concentrations of ATV and its five metabolites up to 36 h after 20, 40 or 80 mg ATV administration. The pharmacokinetic parameters dose normalized to 20 mg are presented as follow (n = 15, mean): unbound fraction 9.38%, maximum plasma concentration 9.52 ng/mL, time to reach maximum plasma concentration 0.98 h, apparent total clearance 742.90 L/h, apparent distribution volume 9005 L, and AUC metabolite/ATV ratios 0.06 for p-OH-ATV, 0.94 for o-OH-ATV, 1.43 for ATV-LAC, 0.25 for p-OH-ATV-LAC and 1.75 for o-OH-ATV-LAC. In conclusion, the methods for simultaneous analysis of ATV and its five metabolites as total plasma concentration and ATV as the unbound plasma concentration showed sensitivity, linearity, precision and accuracy compatible with application in pharmacokinetic studies of single oral dose of 20, 40 or 80 mg ATV.

UPLC-MS/MS method for gemfibrozil determination in plasma with application to a pharmacokinetic study in healthy Brazilian volunteers.

Gemfibrozil (GFZ) is a derivative of fibric acid and is used in the treatment of dyslipidemia. GFZ may affect the metabolism of various drugs, including statins, by inhibiting the sinusoidal influx transporter OATP1B1 and also CYP2C9 and CYP2C8 enzymes. This study presents the development and validation of a rapid, simple, sensitive and reproducible method of GFZ analysis in human plasma using UPLC-MS/MS. The method was applied in a pharmacokinetic study following administration of multiple doses of 600 mg GFZ every 12 h in healthy volunteers (n = 15). GFZ was separated on a C18 column using a mixture of 0.01% formic acid and acetonitrile (40:60, v/v) as the mobile phase at a flow rate of 0.4 mL/min. The method showed linearity in the range from 0.01 µg/mL to 100 µg/mL plasma. The coefficients of variation and the relative standard errors of the accuracy and precision analyses were <15%. The method allowed quantification of plasma concentrations of GFZ in the dose interval of the sixth day of administration of multiple oral doses of GFZ every 12 h. The pharmacokinetic parameters are presented as mean (95% CI): area under the plasma concentration versus time curve 88.84 (72.72-104.96) µg·h/mL, steady state mean plasma concentration 7.40 (6.06-8.75) µg/mL, minimum plasma concentration 1.24 (0.87-1.61) µg/mL, maximum plasma concentration 26.73 (21.31-32.15) µg/mL, time to reach maximum plasma concentration 2.28 (1.42-3.13) h, elimination half-life 2.81 (2.22-3.40) h, apparent total clearance 7.72 (5.85-9.58) L/h, apparent distribution volume 33.97 (18.41-49.53) L. In conclusion, the method for analysis of GFZ in human plasma showed sensitivity, linearity, precision and accuracy compatible with application in pharmacokinetic studies of multiple oral dose of 600 mg GFZ every 12 h.