Coadministration of atazanavir-ritonavir and zinc sulfate: impact on hyperbilirubinemia and pharmacokinetics.
Moyle G , et al.
«Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) as Solvazinc tablets for 14 days. ATV/r and bilirubinconcentration were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentration in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were nosignificant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0-24) were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients.»
Adolescent, Adult, Aged, Anti-HIV Agents, Area Under Curve, Atazanavir Sulfate, Bilirubin, Confidence Intervals, Cross-Over Studies, Drug Administration Schedule, Drug Therapy, Combination, Drug Tolerance, Female, HIV Infections, HIV-1, Humans, Hyperbilirubinemia, Male, Middle Aged, Oligopeptides, Pyridines, Ritonavir, Young Adult, Zinc Sulfate
Zinc sulfate inhibits the enterohepatic cycling of unconjugated bilirubin in subjects with Gilbert's syndrome.
Méndez-Sánchez N , et al.
«We have previously observed that UCB binds to ZnSO4in vitro, and suppressed the biliary bilirubin secretion in the hamster. The aim of this study was designed to investigate whether Zn salts might inhibit the enterohepatic cycling of UCB in subjects with Gilbert s syndrome. Fifteen patients with Gilbert s syndrome and 5 normal healthy volunteers were included in this study according to the following criteria: fastinghyperbilirubinemia, nohemolysis, and free of any medication. Patients were randomly assigned to receive acute o chronic treatment. Subjects treated in acute form and normal healthy volunteers were treated with 40 mg of ZnSO4 in a single dose, where as patients treated in chronic form received 100 mg ZnSO4 in a single dose daily for 7 days. The serum UCB levels (mg/dL) decreased from 2.64 +/- 1.04 to 2.02 +/- 0.87 (p < 0.001) and 1.8 +/- 0.36 to 1.48 +/- 0.32 (p < 0.005) in subjects treated in acute an chronic form respectively, but not in the control group. Whereas, the serum Zn levels (mg/dL) increased from 96.3 +/- 16.8 to 118.8 +/- 19. 5, (p < 0.01) and from 117.6 +/- 8.5 to 130.7 +/- 6.6 (p < 0.03) in subjects treated in acute an chronic form and also in subjects in the control group (98.0 +/- 7.3 to 128.0 +/- 21.9) p < 0.03. This study showed that acute and chronic oral administration of ZnSO4decreased serum UCB levels significantly in subjects with Gilbert s syndrome. Most likely by the inhibition of the "normal" enterohepatic cycling of UCB.»