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1.
AIDS ; 34(13): 1883-1889, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32694416

RESUMEN

OBJECTIVE: For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples. DESIGN: We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients. METHODS: Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated. RESULTS: High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4. CONCLUSION: Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.


Asunto(s)
Fármacos Anti-VIH/líquido cefalorraquídeo , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lamivudine/líquido cefalorraquídeo , Lamivudine/farmacocinética , Zidovudina/líquido cefalorraquídeo , Zidovudina/farmacocinética , Complejo SIDA Demencia/prevención & control , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada , Infecciones por VIH/metabolismo , VIH-1/genética , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Masculino , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Punción Espinal , Estavudina/administración & dosificación , Estavudina/sangre , Estavudina/líquido cefalorraquídeo , Estavudina/uso terapéutico , Carga Viral , Zidovudina/sangre , Zidovudina/uso terapéutico
2.
Medicine (Baltimore) ; 99(22): e20487, 2020 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-32481459

RESUMEN

Simultaneous therapeutic drug monitoring (TDM) of combination antiretroviral therapy (cART) is critical during pregnancy in order to improve clinical follow-up, monitor viral load, and patient adherence to treatment.A modified simple and fast ultra-high performance liquid chromatography coupled with tandem mass spectrometry and electrospray ionization (UPLC-ESI-MS/MS) method was developed and validated according to national and international guidelines for the simultaneous determination of lamivudine (LMV), zidovudine (ZDV), lopinavir (LPV), and ritonavir (RTV) concentrations in 100-µL plasma sample of Human Immunodeficiency Virus (HIV)-positive pregnant women. Protein precipitation using 0.1% formic acid in cold acetonitrile was used for sample preparation. The chromatographic separation was achieved with a run-time of 3.0 minutes and 3-µL injection on an ethylene bridged hybrid C18 column (2.1 µm × 50 mm, 1.7 µm), under gradient conditions using acetonitrile and formic acid (0.1%).The chromatographic method was used to analyze 10 plasma samples from 8 HIV pregnant women as a clinical patient routinely follow-up by applying TDM criteria.The protonated precursor/product ion transitions for LMV (230.18/112.08), ZDV (268.22/127.10), LPV (629.55/447.35), and RTV (721.50/296.20) were recorded in multiple-reaction-monitoring (MRM) mode. The calibration curve was linear in the range of 50-3,000, 75-4,500, 250-15,000, and 25-1,500-ng/mL for LMV, ZDV, LPV, and RTV, respectively. The range of accuracy was 97.2% to 100.1% and precision 3.4% to 12.7%. The method showed specificity and matrix effect values of < 15%. Minimum absolute recovery percentages (%CV) were 90.5 (5.4), 90.8 (5.0), 95.4 (3.5), and 93.7 (6.9), for LMV, ZDV, LPV, and RTV, respectively. Drug concentrations in patient samples had high inter-individual variability with %CV of 91.98%, 77.54%, 53.80%, and 92.16% for ZDV, LMV, LPV, and RTV, respectively. Two of the 8 patients showed no adherence due to the absence of Protease Inhibitors (PIs) levels in plasma.This technique demonstrated to be effective in therapeutic drug monitoring and is intended to be used in population pharmacokinetics specifically for HIV-positive pregnant women.


Asunto(s)
Fármacos Anti-VIH/sangre , Monitoreo de Drogas , Seropositividad para VIH/tratamiento farmacológico , Lamivudine/sangre , Lopinavir/sangre , Ritonavir/sangre , Zidovudina/sangre , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Seguridad del Paciente , Embarazo , Espectrometría de Masas en Tándem , Carga Viral
3.
Pak J Pharm Sci ; 33(1): 49-52, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32122830

RESUMEN

Shenlin Fuzheng Capsule (SLFZC) is a herbal preparation used for HIV/AIDS in Guangxi, China. This study was designed to evaluate the influence of SLFZC on the pharmacokinetics of highly active antiretroviral therapy (HAART) drugs, zidovudine (3'-azido-3'-deoythymidine, AZT), 2',3'-dideoxy-3'-thiacytidine (3TC) and efavirenz (EFV). Thirty-six male SD rats were divided into three groups. Group A was given a combination of AZT, 3TC and EFV (AZT/3TC/EFV). Group B rats were given AZT/3TC/EFV simultaneously with SLFZC. Group C rats were given AZT/3TC/EFV 2h prior to SLFZC. Blood samples were collected at fixed time intervals. Plasma concentration of each antiretroviral drug was tested for calculation of pharmacokinetic parameters. There was significant difference among groups with respect to t1/2 for AZT (F=3.371, P<0.05), but the Student-Newman-Keuls (SNK) pairwise multiple comparison procedure showed no statistical differences in all pairwise comparisons (P>0.05). There were no significant differences among groups in terms of Cmax, T max, AUC0-12h and CL for AZT, and t1/2, Cmax, Tmax, AUC0-12h and CL for 3TC and EFV, respectively. The results indicate that SLFZC has little impact on pharmacokinetic properties of AZT, 3TC and EFV.


Asunto(s)
Alquinos/farmacocinética , Benzoxazinas/farmacocinética , Ciclopropanos/farmacocinética , Interacciones de Hierba-Droga , Lamivudine/farmacocinética , Zidovudina/farmacocinética , Alquinos/sangre , Animales , Benzoxazinas/sangre , Ciclopropanos/sangre , Lamivudine/sangre , Masculino , Ratas , Zidovudina/sangre
4.
Biopharm Drug Dispos ; 40(5-6): 176-187, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30985942

RESUMEN

We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi-elimination pathway mediated by CYP3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug-drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta-analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration-time profile for mirabegron in an sRI population (simulated area under the plasma concentration-time curve (AUC) was within 1.5-times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12-times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.


Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Modelos Biológicos , Insuficiencia Renal/metabolismo , Tiazoles/farmacocinética , Acetanilidas/sangre , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/sangre , Adulto , Anciano , Envejecimiento/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores del Citocromo P-450 CYP2D6/sangre , Inhibidores del Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/sangre , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Desipramina/sangre , Desipramina/farmacocinética , Interacciones Farmacológicas , Femenino , Gemfibrozilo/sangre , Gemfibrozilo/farmacocinética , Glucuronosiltransferasa/metabolismo , Humanos , Itraconazol/sangre , Itraconazol/farmacocinética , Lorazepam/sangre , Lorazepam/farmacocinética , Masculino , Persona de Mediana Edad , Insuficiencia Renal/sangre , Tiazoles/sangre , Adulto Joven , Zidovudina/sangre , Zidovudina/farmacocinética
5.
AIDS Res Hum Retroviruses ; 34(11): 912-915, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30173559

RESUMEN

Clinical trials demonstrated intermittent preventive treatment in pregnancy with mefloquine (MQ) reduced malaria rates among pregnant women, yet an unexpected higher risk of mother-to-child transmission (MTCT) of HIV among HIV-positive women receiving MQ has also been observed. To determine if interactions between antiretroviral drugs (ARVs) and MQ could contribute to the increased MTCT observed in women receiving MQ, we performed a retrospective cross-sectional analysis of ARV plasma concentrations in peripheral blood (maternal plasma) and cord blood (cord plasma) collected at delivery from 186 mothers participating in a randomized clinical trial of MQ (n = 102) compared with placebo (n = 84) in Kenya. Plasma zidovudine (AZT), lamivudine (3TC), and nevirapine (NVP) concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Although only 4% (7/186) reported not using these ARVs, AZT, 3TC, and NVP were all below the limit of detection in 44% of maternal plasma and 42% of cord plasma samples, and proportions were similar between the two study arms. Median concentrations of AZT and 3TC were not significantly lower in the MQ arm compared with the placebo arm for maternal plasma and cord plasma (p > .05). However, median NVP concentrations were significantly lower in the MQ study arm compared with the placebo study arm in both maternal plasma (1,597 ng/mL vs. 2,353 ng/mL, Mann-Whitney Rank Sum, p = .023) and cord plasma (2,038 ng/mL vs. 2,434 ng/mL, p = .048). Reduced NVP concentrations in maternal and cord plasma of women receiving MQ suggest MQ may affect NVP metabolism for both mother and infant. These results highlight the need to evaluate potential drug-drug interactions between candidate antimalarials and ARVs for use in pregnant women.


Asunto(s)
Fármacos Anti-VIH/sangre , Antimaláricos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Malaria/prevención & control , Mefloquina/uso terapéutico , Nevirapina/sangre , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Antimaláricos/efectos adversos , Estudios Transversales , Interacciones Farmacológicas , Femenino , Sangre Fetal/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/transmisión , Humanos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Kenia , Lamivudine/sangre , Lamivudine/uso terapéutico , Mefloquina/efectos adversos , Nevirapina/uso terapéutico , Embarazo , Complicaciones Infecciosas del Embarazo/sangre , Estudios Retrospectivos , Zidovudina/sangre , Zidovudina/uso terapéutico
6.
Biosens Bioelectron ; 111: 82-89, 2018 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-29653420

RESUMEN

Double layered one-by-one imprinted hollow core-shells@ pencil graphite electrode was fabricated for sequential sensing of anti-HIV drugs. For this, two eccentric layers were developed on the surface of vinylated silica nanospheres to obtain double layered one-by-one imprinted solid core-shells. This yielded hollow core-shells on treatment with hydrofluoric acid. The modified hollow core-shells (single layered dual imprinted) evolved competitive diffusion of probe/analyte molecules. However, the corresponding double layered one-by-one imprinted hollow core-shells (outer layer imprinted with Zidovudine, and inner layer with Lamivudine) were found relatively better owing to their bilateral diffusions into molecular cavities, without any competition. The entire work is based on differential pulse anodic stripping voltammetry at double layered one-by-one imprinted hollow core-shells. This resulted in indirect detection of electro inactive targets with limits of detection as low as 0.91 and 0.12 (aqueous sample), 0.94 and 0.13 (blood serum), and 0.99 and 0.20 ng mL-1 (pharmaceutics) for lamivudine and zidovudine, respectively in anti-HIV drug combination.


Asunto(s)
Fármacos Anti-VIH/sangre , Técnicas Electroquímicas/métodos , Lamivudine/sangre , Impresión Molecular/métodos , Polímeros/química , Zidovudina/sangre , Fármacos Anti-VIH/análisis , Técnicas Biosensibles/métodos , Grafito/química , Humanos , Lamivudine/análisis , Límite de Detección , Zidovudina/análisis
7.
Acta Pharmacol Sin ; 38(11): 1554-1565, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28770824

RESUMEN

HIV infection is often associated with liver failure, which alters the pharmacokinetics of many drugs. In this study we investigated whether acute liver failure (ALF) altered the pharmacokinetics of the first-line anti-HIV agent zidovudine (AZT), a P-gp/BCRP substrate, in rats. ALF was induced in rats by injecting thioacetamide (TAA, 300 mg·kg-1·d-1, ip) for 2 days. On the second day after the last injection of TAA, the pharmacokinetics of AZT was investigated following both oral (20 mg/kg) and intravenous (10 mg/kg) administration. ALF significantly increased the plasma concentrations of AZT after both oral and intravenous doses of AZT, but without affecting the urinary excretion of AZT. AZT metabolism was studied in rat hepatic microsomes in vitro, which revealed that hepatic UGT2B7 was the main enzyme responsible for the formation of AZT O-glucuronide (GAZT); ALF markedly impaired AZT metabolism in hepatic microsomes, which was associated with the significantly decreased hepatic UGT2B7 expression. Intestinal absorption of AZT was further studied in rats via in situ single-pass intestinal perfusion. Intestinal P-gp function and intestinal integrity were assessed with rhodamine 123 and FD-70, respectively. We found that ALF significantly downregulated intestinal P-gp expression, and had a smaller effect on intestinal BCRP. Further studies showed that ALF significantly increased the intestinal absorption of both rhodamine 123 and AZT without altering intestinal integrity, thus confirming an impairment of intestinal P-gp function. In conclusion, ALF significantly increases the oral plasma exposure of AZT in rats, a result partly attributed to the impaired function and expression of hepatic UGT2B7 and intestinal P-gp.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Glucuronosiltransferasa/metabolismo , Yeyuno/metabolismo , Fallo Hepático Agudo/enzimología , Hígado/enzimología , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/farmacocinética , Zidovudina/administración & dosificación , Zidovudina/farmacocinética , Administración Intravenosa , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Absorción Intestinal , Masculino , Microsomas Hepáticos/enzimología , Ratas Sprague-Dawley , Eliminación Renal , Inhibidores de la Transcriptasa Inversa/sangre , Tioacetamida , Zidovudina/sangre
8.
J Acquir Immune Defic Syndr ; 72(3): 246-53, 2016 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-26859826

RESUMEN

OBJECTIVES: Zidovudine (AZT) is mainly used to prevent mother-to-child HIV-1 transmission (PMTCT). Despite serious concerns on AZT-associated toxicity, there is little information on pharmacokinetics of intracellular AZT metabolites in infants. METHODS: We conducted a prospective study in 31 HIV-uninfected infants who received AZT for PMTCT. Blood samples were obtained from 14 infants on postdelivery days (PDD) 1, 7, 14, and 28 and from 17 infants at 0 and 4 hours after dosing on PDD-1. Plasma AZT concentrations (pAZT) and intracellular concentrations of AZT-monophosphate (icAZT-MP), diphosphate (icAZT-DP), and triphosphate (icAZT-TP) were determined. RESULTS: Plasma AZT and icAZT-MP concentrations were 2713 nmol/L and 79 fmol/10 cells in PDD-1, but decreased to 1437 nmol/L and 31 fmol/10 cells by PDD-28 (P = 0.02 and P = 0.07 for all PDDs, respectively), whereas those of icAZT-DP and icAZT-TP remained low throughout the sampling period (P = 0.29 and P = 0.61 for all PDDs, respectively) There were no differences in icAZT-TP between infants of the 2 mg/kg 4 times a day dose and 4 mg/kg twice daily dose (P = 0.25), whereas pAZT and icAZT-MP levels were higher in the latter (P < 0.01 and <0.01, respectively). The pAZT and icAZT-MP significantly increased from 0 to 4 hours after dosing (P < 0.001 and <0.001, respectively), whereas icAZT-DP, icAZT-TP levels were not changed (P = 0.41 and 0.33, respectively). CONCLUSIONS: The level of icAZT-TP did not change with age, time, or a single dose despite the wide range of pAZT concentration. A safer dosage needs to be determined because high pAZT levels do not parallel those of icAZT-TP.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Didesoxinucleótidos/farmacocinética , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Nucleótidos de Timina/farmacocinética , Zidovudina/análogos & derivados , Zidovudina/farmacocinética , Adulto , Fármacos Anti-VIH/sangre , Cromatografía Líquida de Alta Presión/métodos , Didesoxinucleótidos/sangre , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , Madres , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Estudios Prospectivos , Nucleótidos de Timina/sangre , Resultado del Tratamiento , Adulto Joven , Zidovudina/sangre
9.
J Mass Spectrom ; 50(6): 783-91, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26169132

RESUMEN

Although zidovudine (AZT) is not the preferred antiretroviral drug for adult HIV-infected patients, it is still widely used in infants for both prevention of mother-to-infant HIV-1 transmission and treatment of HIV-infected children. However, it is difficult to measure intracellular concentrations of AZT metabolites in small blood samples due to their extremely low concentrations in peripheral blood mononuclear cells and interference by endogenous nucleotide triphosphates, residual plasma phosphates and electrolytes. We developed an ultrasensitive assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for measurement of intracellular concentrations of zidovudine (AZT)-monophosphate (AZT-MP), -diphosphate (AZT-DP) and -triphosphate (AZT-TP). The high sensitivity was due to the improvement of peripheral blood mononuclear cells extraction for complete removal of plasma and electrolytes, alkalization of LC buffer and use of alkaline-stable high performance liquid chromatography column and tetrabutylammonium hydroxide as the ion pair. Using this method, the lower limits of quantification of AZT, AZT-MP, -DP and -TP were 6, 6, 10 and 10 fmol per sample, respectively. Accuracy ranged 89-115% and precision was lower than 15% in the quantification range of 6-6000 fmol/sample for plasma AZT and intracellular AZT-MP and 10-10 000 fmol/sample for AZT-DP and -TP. The validation parameters met the international requirements. Among nine AZT-treated HIV-infected adult patients, five had low AZT-TP levels (<10 fmol/10(6) cells). Our assay has high sensitivity and is advantageous for evaluation of AZT phosphates in children and infants based on minimum blood sampling requirement.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Didesoxinucleótidos/sangre , Leucocitos Mononucleares/química , Espectrometría de Masas en Tándem/métodos , Nucleótidos de Timina/sangre , Zidovudina/análogos & derivados , Anciano , Femenino , Humanos , Límite de Detección , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Zidovudina/sangre
10.
J Int Assoc Provid AIDS Care ; 14(2): 116-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25361558

RESUMEN

Pharmacokinetics of lamivudine (3TC)/zidovudine (ZDV) and lopinavir/ritonavir (LPV/r) are described in a gravid 27-year-old HIV-infected woman with gastric bypass. Blood levels were obtained for these medications at time points 0 (predose) and 1, 2, 4, 6, 8, and 12 hours postdose. For these times, the levels (µg/mL) of 3TC were 0.0801, 0.69, 0.339, 0.237, 0.202, 0.108, and 0.0461; the levels of ZDV were 0.0153, 0.433, 0.0717, 0.0481, 0.0107, 0.0214, and 0.00864; the levels of lopinavir (LPV) were 2.45, 2.64, 1.95, 2.78, 3.83, 3.20, and 1.92; and the levels of ritonavir (RTV) were 0.09, 0.10, 0.07, 0.11, 0.15, 0.15, and 0.06. These data suggest that gastric bypass affected these antiretroviral drug levels. A functional, intact small bowel is responsible for absorption of these medications.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Lopinavir/uso terapéutico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Tercer Trimestre del Embarazo/sangre , Ritonavir/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Fármacos Anti-VIH/sangre , Combinación de Medicamentos , Femenino , Derivación Gástrica , Infecciones por VIH/sangre , Humanos , Lamivudine/sangre , Lopinavir/sangre , Embarazo , Complicaciones Infecciosas del Embarazo/sangre , Complicaciones Infecciosas del Embarazo/cirugía , Ritonavir/sangre , Zidovudina/sangre
11.
J Pharm Sci ; 104(1): 244-56, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25393417

RESUMEN

In this study, we aimed to determine the modulatory effects of warfarin (an extensively used anticoagulant drug) and its metabolites on UDP-glucuronosyltransferase (UGT) activity and to assess the potential of warfarin to alter the pharmacokinetics of zidovudine (AZT). The effects of warfarin and its metabolites on glucuronidation were determined using human and rat liver microsomes (HLM and RLM) as well as expressed UGTs. The mechanisms of warfarin-UGT interactions were explored through kinetic characterization and modeling. Pharmacokinetic studies with rats were performed to evaluate the potential of warfarin to alter the pharmacokinetics of AZT. We found that warfarin was an effective modifier of a panel of UGT enzymes. The effects of warfarin on glucuronidation were inhibitory for UGT1A1, 2B7, and 2B17, but activating for UGT1A3. Mixed effects were observed for UGT1A7 and 1A9. Consistent with its inhibitory effects on UGT2B7 activity, warfarin inhibited AZT glucuronidation in HLM (Ki = 74.9-96.3 µM) and RLM (Ki = 190-230 µM). Inhibition of AZT glucuronidation by UGT2B7, HLM, and RLM was also observed with several hydroxylated metabolites of warfarin. Moreover, the systemic exposure (AUC) of AZT in rats was increased by a 1.5- to 2.1-fold upon warfarin coadministration. The elevated AUC was associated with suppressed glucuronidation that was probably attained through a combined action of warfarin and its hydroxylated metabolites. In conclusion, the activities of multiple UGT enzymes can be modulated by warfarin and the nature of modulation was isoform dependent. Also, pharmacokinetic interactions of zidovudine with warfarin were highly possible through inhibition of UGT metabolism.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Anticoagulantes/efectos adversos , Glucuronosiltransferasa/metabolismo , Hígado/efectos de los fármacos , Modelos Biológicos , Warfarina/efectos adversos , Zidovudina/farmacocinética , Animales , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Anticoagulantes/química , Anticoagulantes/farmacología , Disponibilidad Biológica , Biotransformación/efectos de los fármacos , Interacciones Farmacológicas , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucurónidos/sangre , Glucurónidos/metabolismo , Glucuronosiltransferasa/química , Glucuronosiltransferasa/genética , Humanos , Hidroxilación , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Hígado/enzimología , Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Proteínas Recombinantes/metabolismo , Warfarina/análogos & derivados , Warfarina/farmacología , Zidovudina/sangre , Zidovudina/metabolismo , Zidovudina/farmacología
12.
Antivir Ther ; 20(2): 225-33, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25279808

RESUMEN

BACKGROUND: Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC. METHODS: Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV/r:3TC:ZDV(ABC) dose ratios were 2.67:1:2(2), respectively. RESULTS: Using WHO dosage, LPV efficacy target was reached in all weight bands. Given the recommended drug ratios, the dosage for the 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [bid]) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg bid decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria. CONCLUSIONS: This defined a flexible and simple FDC containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4-5.9 kg, 6-9.9 kg, 10-13.9 kg, 14-19.9 kg, 20-24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid.


Asunto(s)
Didesoxinucleósidos/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lamivudine/farmacocinética , Lopinavir/farmacocinética , Modelos Estadísticos , Ritonavir/farmacocinética , Silimarina/farmacocinética , Zidovudina/farmacocinética , Administración Oral , Adolescente , Factores de Edad , Terapia Antirretroviral Altamente Activa , Disponibilidad Biológica , Niño , Preescolar , Ensayos Clínicos como Asunto , Simulación por Computador , Didesoxinucleósidos/administración & dosificación , Didesoxinucleósidos/sangre , Combinación de Medicamentos , Cálculo de Dosificación de Drogas , Monitoreo de Drogas , Femenino , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/crecimiento & desarrollo , Humanos , Lactante , Lamivudine/administración & dosificación , Lamivudine/sangre , Lopinavir/administración & dosificación , Lopinavir/sangre , Masculino , Ritonavir/administración & dosificación , Ritonavir/sangre , Silibina , Silimarina/administración & dosificación , Carga Viral/efectos de los fármacos , Zidovudina/administración & dosificación , Zidovudina/sangre
13.
Mater Sci Eng C Mater Biol Appl ; 39: 105-12, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24863205

RESUMEN

The zidovudine (ZDV) is the first drug approved for the treatment of HIV virus infection. The detection and determination of this drug are very importance in human serum because of its undesirable effects. A new ZDV sensor was fabricated on the basis of nanocomposite of silver nanofilm (Ag-NF) and multiwalled carbon nanotubes (MWCNTs) immobilized on glassy carbon electrode (GCE). The modified electrodes were characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), cyclic voltammetry (CV), and linear sweep voltammetry (LSV) techniques. Results showed that the electrodeposited silver has a nanofilm structure and further electrochemical studies showed that the prepared nanocomposite has high electrocatalytic activity and is appropriate for using in sensors. The amperometric technique under optimal conditions is used for the determination of ZDV ranging from 0.1 to 400ppm (0.37µM-1.5mM) with a low detection limit of 0.04ppm (0.15µM) (S/N=3) and good sensitivity. The prepared sensor possessed accurate and rapid response to ZDV and shows an average recovery of 98.6% in real samples.


Asunto(s)
Fármacos Anti-VIH/sangre , Técnicas Biosensibles/instrumentación , Nanotubos de Carbono/química , Zidovudina/sangre , Técnicas Biosensibles/métodos , Técnicas Electroquímicas , Electrodos , Humanos , Límite de Detección , Nanopartículas del Metal/química , Microscopía Electrónica de Rastreo , Nanocompuestos/química , Plata/química , Espectrometría por Rayos X , Difracción de Rayos X
14.
Antimicrob Agents Chemother ; 57(10): 4801-8, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23877688

RESUMEN

The aims of this study were to describe the pharmacokinetics of zidovudine (ZDV) and its biotransformation to its metabolite, 3*-azido-3*-deoxy-5*-glucuronylthymidine (G-ZDV), in HIV-infected children, to identify factors that influence the pharmacokinetics of ZDV, and to compare and evaluate the doses recommended by the World Health Organization (WHO) and the Food and Drug Administration (FDA). ZDV concentrations in 782 samples and G-ZDV concentrations in 554 samples from 247 children ranging in age from 0.5 to 18 years were retrospectively measured. A population pharmacokinetic model was developed with NONMEM software (version 6.2), and the pharmacokinetics of ZDV were best described by a one-compartment model with first-order absorption and elimination. The effect of body weight on the apparent elimination clearance and volume of distribution was significant. The mean population parameter estimates were as follows: absorption rate, 2.86 h(-1); apparent elimination clearance, 89.7 liters · h(-1) (between-subject variability, 0.701 liters · h(-1)); apparent volume of distribution, 229 liters (between-subject variability, 0.807 liters); metabolic formation rate constant, 12.6 h(-1) (between-subject variability, 0.352 h(-1)); and elimination rate constant of G-ZDV, 2.27 h(-1). On the basis of simulations with FDA and WHO dosing recommendations, the probabilities of observing efficient exposures (doses resulting in exposures of between 3 and 5 mg/liter · h) with less adverse events (doses resulting in exposures below 8.4 mg/liter · h) were higher when the FDA recommendations than when the WHO recommendations were followed. In order to improve the FDA recommendations, ZDV doses should be reconsidered for the weight band (WB) of 20 to 40 kg. The most appropriate doses should be decreased from 9 to 8 mg/kg of body weight twice a day (BID) for the WB from 20 to 29.9 kg and from 300 to 250 mg BID for the WB from 30 to 39.9 kg. The highest dose, 300 mg BID, should be started from body weights of 40 kg.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Zidovudina/farmacocinética , Adolescente , Fármacos Anti-VIH/sangre , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Lactante , Masculino , Estados Unidos , United States Food and Drug Administration , Organización Mundial de la Salud , Zidovudina/sangre
15.
Artículo en Inglés | MEDLINE | ID: mdl-23416289

RESUMEN

A selective and sensitive high performance liquid chromatography-tandem mass spectrometry method has been developed and validated for simultaneous determination of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in human plasma. After Solid phase extraction (SPE), analytes and ISTDs were run on Peerless Basic C18 column with an injection volume of 3µL and run time of 3.0min. An isocratic mobile phase of 0.1% formic acid in water:methanol (15:85, v/v) was used with positive mass spectrometric detection. The method was validated over a concentration range of 5-1500ng/mL for ZDV and 3TC and over the concentration range of 10-3000ng/mL for NVP. The intraday and interday precision and accuracy across four validation runs were ranged from 1.6 to 10.1% and 93.8 to 110.8% respectively.


Asunto(s)
Fármacos Anti-VIH/sangre , Lamivudine/sangre , Nevirapina/sangre , Espectrometría de Masas en Tándem/métodos , Zidovudina/sangre , Cromatografía Liquida/métodos , Humanos , Masculino , Sensibilidad y Especificidad , Extracción en Fase Sólida
16.
Drug Test Anal ; 5(6): 485-91, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22374835

RESUMEN

A simple, rapid, and sensitive high performance liquid chromatographic method with UV detection has been developed and validated according to the FDA guidelines for the quantitation of zidovudine (ZDV), lamivudine (LMV), and nevirapine (NVR) in human plasma. The sample was prepared by simple liquid-liquid extraction. Chromatographic separation was carried out in a Hypersil BDS, C(18) column (250 mm × 4.6 mm; 5 µm particle size) with simple mobile phase composition of 0.1 M ammonium acetate buffer in 0.5% acetic acid, v/v and methanol (40:60, v/v) at a flow rate of 0.85 ml min(-1) where detector was set at 270 nm with a total run time of 10 min which is very short for simultaneous estimation of three analytes in plasma. The method was linear over the concentration range of 50-3000, 50-2000 and 10-3000 ng ml(-1) with lower limit of quantifications (LLOQ) of 50, 50, and 10 ng ml(-1) for ZDV, LMV, and NVR, respectively. Accuracy and precision values of both within-run and between-run obtained from six different sets of three quality control (QC) samples along with the LLOQ analyzed in separate occasions for all the analytes ranged from 94.47-99.71% and 0.298-3.507%, respectively. Extraction recovery of analytes in plasma samples was above 90.16%. In stability tests, all the analytes in human plasma were stable during storage and assay procedure. The developed and validated method was successfully applied to quantitative determination of the three analytes in plasma for pharmacokinetic study in 12 healthy human volunteers.


Asunto(s)
Fármacos Anti-VIH/sangre , Cromatografía Líquida de Alta Presión/métodos , Lamivudine/sangre , Nevirapina/sangre , Zidovudina/sangre , Humanos , Límite de Detección , Extracción Líquido-Líquido/métodos
17.
J Acquir Immune Defic Syndr ; 61(5): 593-9, 2012 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-23187888

RESUMEN

OBJECTIVE: Phase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. STUDY DESIGN: We administered a microdose (100 µg) of C-labeled drug (ZDV or tenofovir disoproxil fumarate) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and CD4 cells were measured by accelerator mass spectrometry. RESULTS: The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 µg-300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4 cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4 cells and PBMCs. CONCLUSIONS: Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. Accelerator mass spectrometry shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs.


Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Didesoxinucleótidos/administración & dosificación , Didesoxinucleótidos/farmacocinética , Organofosfonatos/administración & dosificación , Organofosfonatos/farmacocinética , Nucleótidos de Timina/administración & dosificación , Nucleótidos de Timina/farmacocinética , Zidovudina/análogos & derivados , Adenina/administración & dosificación , Adenina/sangre , Adenina/farmacocinética , Adulto , Fármacos Anti-VIH/sangre , Disponibilidad Biológica , Linfocitos T CD4-Positivos/metabolismo , Radioisótopos de Carbono , Didesoxinucleótidos/sangre , Femenino , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Organofosfonatos/sangre , Fosforilación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/farmacocinética , Tenofovir , Nucleótidos de Timina/sangre , Zidovudina/administración & dosificación , Zidovudina/sangre , Zidovudina/farmacocinética
18.
Analyst ; 137(18): 4327-34, 2012 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-22858583

RESUMEN

A methodology based on micellar liquid chromatography to monitor five antiretroviral drugs (lamivudine, stavudine, tenofovir, zidovudine and efavirenz) was proposed. Antiretrovirals were studied in sets of three, corresponding to each highly active antiretroviral therapy (HAART) regime, prescribed to acquired immunodeficiency syndrome (AIDS)-infected patients. Four aqueous micellar mobile phases buffered at pH 7 were optimized to separate these compounds, using sodium dodecyl sulfate as the tensioactive, and 1-propanol or 1-pentanol as the organic modifier. The composition of each mobile phase was optimized for each antiretroviral. The common separation conditions were: C18 apolar column (125 × 4.6 mm, 5 µm particle size), UV detection set at 214 nm, and mobile phase running at 1 mL min(-1) without controlling the temperature. The finally suggested method was validated for five analysed antiretroviral drugs following the US Food and Drug Administration guidelines in terms of: linearity between 0.5 and 50 ppm (r(2) > 0.9995), sensitivity (LOD lower than 0.25 ppm), intra- and inter-day precision (<7.1 and <5.2%, respectively) and accuracy (recovery 88.5-105.3% and 93.5-101.3%, respectively), as well as robustness (<6.5%). The proposed method was used to monitor the level of antiretrovirals in the serum of AIDS patients. The suggested methodology was found to be useful in the routine analysis of antiretrovirals in serum samples.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa , Monitoreo de Drogas , Síndrome de Inmunodeficiencia Adquirida/sangre , Adenina/análogos & derivados , Adenina/sangre , Adenina/uso terapéutico , Alquinos , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/sangre , Benzoxazinas/uso terapéutico , Cromatografía Liquida , Ciclopropanos , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Organofosfonatos/sangre , Organofosfonatos/uso terapéutico , Estavudina/sangre , Estavudina/uso terapéutico , Tenofovir , Zidovudina/sangre , Zidovudina/uso terapéutico
19.
IUBMB Life ; 64(5): 443-9, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22473795

RESUMEN

The nucleoside reverse transcriptase inhibitors lamivudine and zidovudine and the protease inhibitors lopinavir and ritonavir are currently used in anti-human immunodeficiency virus (HIV) therapy. Here, a high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method, using a hybrid quadrupole time-of-flight mass analyzer, is reported for the simultaneous quantification of lamivudine, lopinavir, ritonavir, and zidovudine in plasma of HIV-infected patients. The volume of plasma sample was 600 µL. Plasma samples were extracted by solid-phase using 1 cc Oasis HLB Cartridge (divinylbenzene and N-vinylpyrrolidone) and evaporated in a water bath under nitrogen stream. The extracted samples were reconstituted with 100-µL methanol. Five microliters of the reconstituted samples were injected into a HPLC-MS/MS apparatus, and the analytes were eluted on a Vydac column (250 × 1.0 mm i.d.) filled with 3-µm C(18) particles. The mobile phase was delivered at 70 µL/min with a linear gradient elution, both acetonitrile and ultrapure water solvents contained 0.2% formic acid. The calibration curves were linear from 0.47 to 20 ng/mL. The absolute recovery ranged between 91 and 107%. The minimal concentration of lamivudine, lopinavir, ritonavir, and zidovudine detectable by HPLC-MS/MS is 0.47, 0.28, 0.30, and 0.66 ng/mL, respectively. The great advantage of the new HPLC-MS/MS method here reported is the possibility to achieve a very high specificity toward the selected anti-HIV drugs, despite the simple and rapid sample preparation. Moreover, this method is easily extendible to the analysis of co-administrated drugs.


Asunto(s)
Fármacos Anti-VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Lamivudine/sangre , Lopinavir/sangre , Ritonavir/sangre , Zidovudina/sangre , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/uso terapéutico , Calibración , Cromatografía Líquida de Alta Presión/normas , Infecciones por VIH/sangre , Humanos , Lamivudine/aislamiento & purificación , Lamivudine/uso terapéutico , Límite de Detección , Lopinavir/aislamiento & purificación , Lopinavir/uso terapéutico , Estándares de Referencia , Reproducibilidad de los Resultados , Ritonavir/aislamiento & purificación , Ritonavir/uso terapéutico , Espectrometría de Masas en Tándem/normas , Zidovudina/aislamiento & purificación , Zidovudina/uso terapéutico
20.
Biomed Chromatogr ; 26(1): 12-20, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21465499

RESUMEN

A sensitive LC/MS/MS assay for determining zidovudine (ZDV) and lamivudine (3TC) in human plasma was validated to support antiretroviral pharmacology research programs. After addition of stable labeled isotopic zidovudine (ZDV-IS) and lamivudine (3TC-IS) as internal standard, a solid-phase extraction was performed with an Oasis HLB 1 cm(3) cartridge, with recoveries of 92.3% for ZDV and 93.9% for 3TC. A Phenomonex Synergi Hydro-RP (2.0 ×150 mm) reversed-phase analytical column was utilized for chromatographic separation. The mobile phase consisted of an aqueous solution of 15% acetonitrile and 0.1% acetic acid. Detection was accomplished by ESI/MS/MS in the positive ion mode, monitoring 268/127, 271/130, 230/112 and 233/115 transitions, for ZDV, ZDV-IS, 3TC and 3TC-IS, respectively. The method was linear from 1 to 3000 ng/mL with a minimum quantifiable limit of 1 ng/mL when 100 µL of plasma was analyzed. Validation results demonstrated high accuracy (≤8.3% deviation) and high precision (≤10% CV) for the quality control samples. The method was also shown to be specific and reproducible. The value of the high sensitivity was demonstrated by quantitation of approximately 100 existing samples that had ZDV below the limit of quantitation using a previously validated, less sensitive HPLC-UV method utilized in the laboratory.


Asunto(s)
Cromatografía Liquida/métodos , Lamivudine/sangre , Espectrometría de Masas en Tándem/métodos , Zidovudina/sangre , Estabilidad de Medicamentos , Humanos , Lamivudine/química , Modelos Lineales , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Extracción en Fase Sólida , Zidovudina/química
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