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Background: Therapeutic drug monitoring is useful in the treatment of tuberculosis to assure adequate exposure, minimize antibiotic resistance, and reduce toxicity. Salivary therapeutic drug monitoring could reduce the risks, burden, and costs of blood-based therapeutic drug monitoring. This systematic review compared human pharmacokinetics of antituberculosis drugs in saliva and blood to determine if salivary therapeutic drug monitoring could be a promising alternative.Methods: On December 2, 2016, PubMed and the Institute for Scientific Information Web of Knowledge were searched for pharmacokinetic studies reporting human salivary and blood concentrations of antituberculosis drugs. Data on study population, study design, analytical method, salivary Cmax, salivary area under the time-concentration curve, plasma/serum Cmax, plasma/serum area under the time-concentration curve, and saliva-plasma or saliva-serum ratio were extracted. All included articles were assessed for risk of bias.Results: In total, 42 studies were included in this systematic review. For the majority of antituberculosis drugs, including the first-line drugs ethambutol and pyrazinamide, no pharmacokinetic studies in saliva were found. For amikacin, pharmacokinetic studies without saliva-plasma or saliva-serum ratios were found.Conclusions: For gatifloxacin and linezolid, salivary therapeutic drug monitoring is likely possible due to a narrow range of saliva-plasma and saliva-serum ratios. For isoniazid, rifampicin, moxifloxacin, ofloxacin, and clarithromycin, salivary therapeutic drug monitoring might be possible; however, a large variability in saliva-plasma and saliva-serum ratios was observed. Unfortunately, sali-vary therapeutic drug monitoring is probably not possible for doripenem and amoxicillin/clavulanate, as a result of very low salivary drug concentrations.

Background: Therapeutic drug monitoring is useful in the treatment of tuberculosis to assure adequate exposure, minimize antibiotic resistance, and reduce toxicity. Salivary therapeutic drug monitoring could reduce the risks, burden, and costs of blood-based therapeutic drug monitoring. This systematic review compared human pharmacokinetics of antituberculosis drugs in saliva and blood to determine if salivary therapeutic drug monitoring could be a promising alternative. Methods: On December 2, 2016, PubMed and the Institute for Scientific Information Web of Knowledge were searched for pharmacokinetic studies reporting human salivary and blood concentrations of antituberculosis drugs. Data on study population, study design, analytical method, salivary Cmax, salivary area under the time-concentration curve, plasma/serum Cmax, plasma/serum area under the time-concentration curve, and saliva-plasma or saliva-serum ratio were extracted. All included articles were assessed for risk of bias. Results: In total, 42 studies were included in this systematic review. For the majority of antituberculosis drugs, including the first-line drugs ethambutol and pyrazinamide, no pharmacokinetic studies in saliva were found. For amikacin, pharmacokinetic studies without saliva-plasma or saliva-serum ratios were found. Conclusions: For gatifloxacin and linezolid, salivary therapeutic drug monitoring is likely possible due to a narrow range of saliva-plasma and saliva-serum ratios. For isoniazid, rifampicin, moxifloxacin, ofloxacin, and clarithromycin, salivary therapeutic drug monitoring might be possible; however, a large variability in saliva-plasma and saliva-serum ratios was observed. Unfortunately, sali-vary therapeutic drug monitoring is probably not possible for doripenem and amoxicillin/clavulanate, as a result of very low salivary drug concentrations.

The authors developed a simple and sensitive, fully validated HPLC-UV method for the determination of both 5-FU and its metabolite DHFU in small-volume plasma samples. The analytes were separated on a 4.6 X 250 mm ID Atlantis dC18 5-mum column with isocratic elution at room temperature. Chlorouracil was used as internal standard. The analytes were detected with an UV diode array detector. DHFU was detected at 205 run, 5-FU at 266 nm, and chlorouracil at both wavelengths. The limits of quantification in plasma were 0.040 mug /mL for 5-FU and 0.075 mug/mL for DHFU. Linearity, accuracy, precision, recovery, dilution, freeze-thaw stability, and stability in the sample compartment were evaluated. The method appeared linear over a range from 0.04 to 15.90 mug/mL for 5-FU and from 0.075 to 3.84 mug/mL for DHFU. The method appeared very suitable for therapeutic drug monitoring and pharmacokinetic studies of 5-FU because of its simple extraction and small sample volume. Problems in earlier published methods with interfering peaks and variable retention times were overcome. The method appeared also to be suitable for detection of uracil and its metabolite dihydrouracil in plasma.

The authors developed a simple and sensitive, fully validated HPLC-UV method for the determination of both 5-FU and its metabolite DHFU in small-volume plasma samples. The analytes were separated on a 4.6 X 250 mm ID Atlantis dC18 5-mum column with isocratic elution at room temperature. Chlorouracil was used as internal standard. The analytes were detected with an UV diode array detector. DHFU was detected at 205 run, 5-FU at 266 nm, and chlorouracil at both wavelengths. The limits of quantification in plasma were 0.040 mug /mL for 5-FU and 0.075 mug/mL for DHFU. Linearity, accuracy, precision, recovery, dilution, freeze-thaw stability, and stability in the sample compartment were evaluated. The method appeared linear over a range from 0.04 to 15.90 mug/mL for 5-FU and from 0.075 to 3.84 mug/mL for DHFU. The method appeared very suitable for therapeutic drug monitoring and pharmacokinetic studies of 5-FU because of its simple extraction and small sample volume. Problems in earlier published methods with interfering peaks and variable retention times were overcome. The method appeared also to be suitable for detection of uracil and its metabolite dihydrouracil in plasma.

A method to determine intracellular vincristine concentrations in vivo in leukemic cells of patients is useful to investigate mechanisms of vincristine resistance. We developed a high-performance liquid chromatographic (HPLC) method to measure vincristine concentrations in human mononuclear cells (MNC). This method, with on-line column solid-phase extraction and electrochemical detection, previously developed for determination of vincristine concentrations in human plasma, was validated for determination of intracellular vincristine concentrations over a range of 1.17 to 50.8 mug/L with a lower limit of quantitation (LOQ) of 1.17 mug/L. Linearity of the relationship between concentration and response was characterized by a slope (sd) of 0.0683 (0.0008), an intercept (sd) of 0.0004 mug/L (0.0085), and a regression coefficient of 0.997 (P = 0.05). Maximum bias and within-day and between-day coefficients of variation (CV) were 14.2%, 4.8%, and 5.7%, respectively. The HPLC detector response did not interfere with the vincristine peaks of five independent MNC sources. The method was used successfully to measure intracellular vincristine concentrations in 8 of 35 bone marrow MNC samples of children newly diagnosed with acute lymphoblastic leukemia (ALL), 3 days after the first injection of 1.5 mg/m(2) vincristine. Vincristine concentrations were in the range of 4.0 to 26.4 mug/L, which was 5 to 20 times the bone marrow plasma concentration. The described HPLC method is accurate and precise and is suitable for detection of intracellular vincristine concentrations in MNC of children with ALL. The results confirm that in vivo vincristine accumulates in bone marrow MNC of patients.

A method to determine intracellular vincristine concentrations in vivo in leukemic cells of patients is useful to investigate mechanisms of vincristine resistance. We developed a high-performance liquid chromatographic (HPLC) method to measure vincristine concentrations in human mononuclear cells (MNC). This method, with on-line column solid-phase extraction and electrochemical detection, previously developed for determination of vincristine concentrations in human plasma, was validated for determination of intracellular vincristine concentrations over a range of 1.17 to 50.8 mug/L with a lower limit of quantitation (LOQ) of 1.17 mug/L. Linearity of the relationship between concentration and response was characterized by a slope (sd) of 0.0683 (0.0008), an intercept (sd) of 0.0004 mug/L (0.0085), and a regression coefficient of 0.997 (P = 0.05). Maximum bias and within-day and between-day coefficients of variation (CV) were 14.2%, 4.8%, and 5.7%, respectively. The HPLC detector response did not interfere with the vincristine peaks of five independent MNC sources. The method was used successfully to measure intracellular vincristine concentrations in 8 of 35 bone marrow MNC samples of children newly diagnosed with acute lymphoblastic leukemia (ALL), 3 days after the first injection of 1.5 mg/m(2) vincristine. Vincristine concentrations were in the range of 4.0 to 26.4 mug/L, which was 5 to 20 times the bone marrow plasma concentration. The described HPLC method is accurate and precise and is suitable for detection of intracellular vincristine concentrations in MNC of children with ALL. The results confirm that in vivo vincristine accumulates in bone marrow MNC of patients.