Effects of Gender, AIDS, and Acetylator Status on Intrapulmonary Concentrations of Isoniazid

Conte, John E.; Golden, Jeffrey A.; McQuitty, Mari; Kipps, Juliana; Duncan, Sheila; McKenna, Elaine; Zurlinden, Elisabeth

doi:10.1128/aac.46.9.3112.2002

Cited by 16 publications

(25 citation statements)

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“…There were no significant differences between slow and fast acetylators. On the other hand, the occurrence of adverse drug reactions was in agreement with other studies which demonstrated that the peripheral neuropathies are more likely to occur early in patients having a low speed of acetylation, suggesting that INH blood levels are high in this group (Comte et al, 2002(Comte et al, , pp.2358(Comte et al, -2364Yee et al,2003Yee et al, , pp.1472Yee et al, -1477. It is obvious that patients with a fast speed of acetylation may experience hepatitis complications long term as reported in the literature (Mitchell et al,1975, pp.70-79;Steele et al,1991, pp.465-71;Huang et al, 2002, pp.883-889), but it was not possible to observe it in our short course treatment time of two months.…”

Section: Discussionsupporting

confidence: 80%

“…Some data demonstrated HIV/AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma (Comte et al, 2002(Comte et al, , pp.2358(Comte et al, -2364Kimerling et al,1998Kimerling et al, , pp.1178Kimerling et al, -1183, while other studies showed a significant reduction of isoniazid and rifampin concentrations in serum of non-HIV-infected patients with tuberculosis who received directly observed therapy (Peloquin et al, 1997(Peloquin et al, , pp.2670(Peloquin et al, -2679. In our study, even though no significant correlation was found for the influence of TB or HIV illness on the acetylator phenotype, a rough analysis of the trends indicated that the ratios of % AcINH tend to shift towards higher values in TB patients as compared to a healthy population without deteriorating the trimodal profile, meaning that the effect of TB or HIV would modify only the proportions between slow, intermediate and fast categories.…”

Section: Discussionmentioning

confidence: 99%

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Determination of Isoniazid Acetylator Phenotype and its Clinical Implication in Rwandan Tuberculosis Patients

Mukanyangezi¹,

Kadima²,

Musemakweri³

2015

RWJour

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The purpose was to determine the normal profile of the isoniazid acetylator phenotype, the effect of tuberculosis (TB) on the profile, and the impact of the profile on early clinical responses following a treatment with the first line drug regimen. The study sample comprised 20 healthy volunteers and 22 TB naive patients. The tests for TB and HIV were conducted in the laboratory of the University Teaching Hospital Butare (CHUB). The phenotype was achieved by measuring the percentage of acetylisoniazid in the urine after a unique oral dose of isoniazid 10 mg/kg. TB patients were treated for two months with standard regimen combining rifampicin, isoniazid, pyrazinamide and ethambutol. A trimodal distribution profile was observed in both the healthy and tuberculosis groups, giving 30% versus 13.6% as slow acetylators, 45% versus 54.5% as intermediate acetylators, and 25% versus 23.2% as fast acetylators respectively. After a 2-month treatment of the TB patients, the sputum smear cultures were negative in about 81% independent of the acetylator or HIV status. Early side effects experienced were dominated by peripheral neuropathies mostly in slow and intermediate acetylators.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Determination of Isoniazid Acetylator Phenotype and its Clinical Implication in Rwandan Tuberculosis Patients

Mukanyangezi¹,

Kadima²,

Musemakweri³

2015

RWJour

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“…Twenty-five subjects in the 150-mg-dose group were assigned to one of five groups of five subjects each according to the time of bronchoscopy: 2, 4, 8, 12, and 24 h following the last dose. Thirty-five subjects in the 300-mgdose group were assigned to one of seven groups of five subjects each according to the time of bronchoscopy: 2, 4,6,8,12,24, and 48 h following the last dose. The 2-and 4-h time periods were chosen to approximate the peak (C max ) intrapulmonary concentration of cethromycin; the 8-h time was chosen as an approximate midpoint between the C max and minimum concentration of drug in serum (C min ) (24 h) in a once-daily dosing regimen.…”

Section: Methodsmentioning

confidence: 99%

“…Techniques for the in vivo measurement of the concentration of antibiotics in ELF and AC have been reported previously (4)(5)(6)(7)(8)(9). The purpose of this investigation was to determine the steady-state plasma and intrapulmonary pharmacokinetic and pharmacodynamic parameters of two dosage regimens of orally administered cethromycin in healthy volunteers.…”

mentioning

confidence: 99%

Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

Conte

Golden²,

Kipps³

et al. 2004

Antimicrob Agents Chemother

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The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C max /90% minimum inhibitory concentration (MIC 90 ) ratios, area under the concentration-time curve (AUC)/MIC 90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC 90 during the dosing interval (%T > MIC 90 ) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C max (mean ؎ standard deviations), AUC 0-24 , and half-life for plasma were 0.181 ؎ 0.084 g/ml, 0.902 ؎ 0.469 g · h/ml, and 4.85 ؎ 1.10 h, respectively; for ELF the values were 0.9 ؎ 0.2 g/ml, 11.4 g · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ؎ 6.4 g/ml, 160.8 g · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C max (mean ؎ standard deviations), AUC 0-24 , and half-life for plasma were 0.500 ؎ 0.168 g/ml, 3.067 ؎ 1.205 g · h/ml, and 4.94 ؎ 0.66 h, respectively; for ELF the values were 2.7 ؎ 2.0 g/ml, 24.15 g · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ؎ 38.7 g/ml, 636.2 g · h/ml, and 11.6 h, respectively. We concluded that the C max /MIC 90 ratios, AUC/MIC 90 ratios, %T > MIC 90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.Cethromycin is an investigational ketolide antibiotic that is active against common respiratory pathogens, such as Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, group A streptococci, and Streptococcus viridans (14,15,17,18,29). Cethromycin is also active, in vitro and in a murine model, against Mycobacterium avium infection (10), and related macrolides are active against other mycobacteria (12, 21). Doses of cethromycin ranging from 100 to 1,200 mg have been administered to humans in phase I clinical studies. The plasma elimination half-life (t 1/2 ) ranges from 3.6 to 6.7 h (R. S. Pradhan, L. E. Gustavson, D. D. Londo, Y. Shang, J. Zhang, and M. Paris, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2138, 2000). The maximum concentration of drug in serum (C max ), area under the concentration-time curve from 0 to 24...

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“…However, when antitubercular drugs are administered orally, drug concentrations in plasma and the lungs are well below the suggested therapeutic range in some patients (6)(7)(8). Additionally, the fraction of an oral dose of drug delivered to the lungs that can access granulomas, tubercles, or lesions which have very poor blood supply may be small (9).…”

Section: Introductionmentioning

confidence: 99%

Isoxyl Aerosols for Tuberculosis Treatment: Preparation and Characterization of Particles

Wang

Hickey

2010

AAPS PharmSciTech

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Abstract. Isoxyl is a potent antituberculosis drug effective in treating various multidrug-resistant strains in the absence of known side effects. Isoxyl has been used exclusively, but infrequently, via the oral route and has exhibited very poor and highly variable bioavailability due to its sparing solubility in water. These properties resulted in failure of some clinical trials and, consequently, isoxyl's use has been limited. Delivery of isoxyl to the lungs, a major site of Mycobacterium tuberculosis infection, is an attractive alternative route of administration that may rescue this abandoned drug for a disease that urgently requires new therapies. Particles for pulmonary delivery were prepared by antisolvent precipitation. Nanofibers with a width of 200 nm were obtained by injecting isoxyl solution in ethanol to water at a volume ratio of solvent to antisolvent of 1:5. Based on this preliminary result, a well-controlled method, involving nozzle mixing, was employed to prepare isoxyl particles. All the particles were 200 to 400 nm in width but had different lengths depending on properties of the solvents. However, generating these nanoparticles by simultaneous spray drying produced isoxyl microparticles (Feret's diameter, 1.19-1.77 μm) with no discernible nanoparticle substructure. The bulking agent, mannitol, helped to prevent these nanoparticles from agglomeration during process and resulted in nanoparticle aggregates in micron-sized superstructures. Future studies will focus on understanding difference of these isoxyl microparticles and nanoparticles/nanoparticle aggregates in terms of in vivo disposition and efficacy.

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Effects of Gender, AIDS, and Acetylator Status on Intrapulmonary Concentrations of Isoniazid

Cited by 16 publications

References 0 publications

Determination of Isoniazid Acetylator Phenotype and its Clinical Implication in Rwandan Tuberculosis Patients

Determination of Isoniazid Acetylator Phenotype and its Clinical Implication in Rwandan Tuberculosis Patients

Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

Isoxyl Aerosols for Tuberculosis Treatment: Preparation and Characterization of Particles

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