Functional intestinal barrier, absorption and bioavailability of Rifampin, Isoniazid and Pyrazinamide in patients with active pulmunary tuberculosis

Reduced antituberculosis drugs concentrations are associated with Mycobacterium tuberculosis resistance, mostly in patients in irregular but also in directly observed treatment. This study aims to evaluate intestinal permeability and bioavailability of rifampin (R), isoniazid (I) and pyrazinamide (P) in patients with active pulmonary tuberculosis. A controlled cross sectional study evaluated intestinal permeability from 56 consecutive active pulmonary tuberculosis (TB) patients who attended Carlos Ribeiro Health Unit in Fortaleza, Ceará, northeast of Brazil, from July 2004 to December 2005. The Thirty who first came were selected to have R, I and P serum concentration dosed. Twenty nine healthy controls were select among health professionals, their relatives and neighboring. To access intestinal permeability lactulose/manitol (L/M) test was performed by HPLC in urine samples collected during five hours. To access bioavailability two blood samples were collect at 2 and 6 hours after drug ingestion. Demographic information was recorded from all volunteers. Mean age was 39.2 ± 15 years in cases and 34 ± 11.0 in controls (p=0.61); 71.4% cases and 65.5% controls were men (p=0.57). Lactulose urinary excretion was significantly lower in TB patients (median 0.1721%; range 0.0-5.0139) than in controls (median 0.4301%; range 0.2125-2.064) (p=0.0194); median manitol excretion in cases was 17.9910% (1.9567-71.5446) and in controls, 24.39894% (range 1.3883-63.0539) (p=0.147) and the lactulose/manitol ratio was of 0.0095 (range 0.0-0.0759) in cases and 0.0153 (0.0-0.0136) in controls (p=0.0698). Maximum means seric rifampin concentration in cases was1.46 ± 0.72 µg/ml and in controls, 3.07 ± 6.69µg/ml (p<0.001); maximum means seric isoniazid concentration was 2.62 ± 1.53 µg/ml in cases and 0.76 ± 1.98 µg/ml in controls (p=0.057); maximum means seric pirazinamide concentratio was 44.10 ± 10.40 µg/ml in cases and 12.02 ± 36.32 µg/ml in controls (p=0.007). Four cases (13.3%) had all tested drugs serum concentrations under expected normal; 21/30 (70.0%) had expected normal concentrations only for one drug (pyrazinamide) and 5/30 (16.7%) for 2 drugs only (pirazinamide and isoniazid). None of the cases had expected concentration levels for all 3 drugs, simultaneously. In conclusion, there was lesion in the functional intestinal barrier and malabsorption for rifampin and isoniazid in active pulmonary TB patients suggesting it is necessary a deeper evaluation of measures to reduce malabsorption, since only these drugs are used during last the four months of treatment.Baixas concentrações séricas de drogas antituberculose podem ser causa da resistência de Mycobacterium tuberculosis às drogas utilizadas para tratamento, a qual é mais freqüente em pacientes em tratamento irregular, mas pode ser verificada em pacientes em tratamento diretamente observado. Os objetivos desse estudo foram avaliar a permeabilidade intestinal e a biodisponibilidade de rifampicina, isoniazida e pirazinamida em pacientes com tuberculose pulmonar ativa. Realizou-se estudo transversal controlado. No período entre julho de 2004 e dezembro de 2005 foram selecionados 56 pacientes consecutivos com tuberculose pulmonar ativa, atendidos no Centro de Saúde Carlos Ribeiro em Fortaleza, Ceará e 29 controles sadios recrutados entre profissionais de saúde, seus familiares e vizinhos para avaliação da permeabilidade intestinal. Foram coletadas informações sociodemográficas e exames bioquímicos e realizou-se o teste de lactulose/manitol de todos. Os primeiros 30 casos de tuberculose e os 29 controles dessa amostra foram selecionados para a avaliação da biodisponibilidade sérica de rifampicina, isoniazida e pirazinamida em amostras coletadas duas horas e seis horas depois da ingestão. A média de idade dos casos foi de 39,2 ± 15 anos e a dos controles 34 ± 11,0 (p=0,61). Eram do sexo masculino 71 % dos casos e 66% dos controles (p=0,57). O peso médio dos casos (52,4 ± 6,3 kg) foi significativamente menor do que o dos controles (71,1 ± 14,0 kg) (p=0,014). Verificou-se menor excreção de lactulose entre os casos (mediana de 0,1721%; variando de 0,0-5.0139%) do que entre os controles (0,4301%; variando de 0,0-2,064) (p=0,049%); a excreção de manitol entre os casos foi 17,9910% (1,9567-71,5446%) e entre controles foi de 24,3899% (1,3883-63,0539%) (p=0,147); a relação lactulose/manitol foi de 0,0095 (0,0-0,0759%) entre os casos e 0,0136 (0,0-0,0136%) entre os controles (p=0,018). A concentração sérica máxima de rifampicina teve média de 1,46 ± 0,72 µg/ml nos casos e de 6,69 ± 3,07 µg/ml nos controles (p