Clinical Pharmacokinetics of Rifampicin
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After oral administration on an empty stomach, the absorption of rifampicin (rifampin) is rapid and practically complete.
With a single 600mg dose, peak serum concentrations of the order of 10μg/ml generally occur 2 hours after administration. The half-life of rifampicin for this dose level is of the order of 2.5 hours.
The amount of rifampicin extracted by the liver during its first passage through the hepatoportal system and transferred to bile is of relevance for the time course of distribution of the antibiotic in the blood compartment. With doses of the order of 300 to 450mg, the excretory capacity of the liver for the antibiotic is saturated. As a consequence, increasing the dose of antibiotic results in a more than proportional increase in serum concentrations.
On repeated administration, and most likely as a consequence of self-induced (autoinduction) metabolism, the rate of disappearance of rifampicin from the blood compartment increases in the early phase of treatment, the phenomenon affecting mainly the levels following the peak, with a consequent reduction in half-life.
Approximately 80% of rifampicin is transported in blood bound to plasma proteins, mainly albumin. Rifampicin is well distributed, although to a different degree, in the various tissues of the human body. Probably in the hepatocyte, rifampicin undergoes a process of desacelylation. The metabolic derivative, desacetylrifampicin, is more polar than the parent compound, and microbiologically active. This metabolite accounts for the majority of the antibacterial activity in the bile. Rifampicin is almost equally excreted in the bile and urine, the recovery in the 2 fluids being of the same order of magnitude.
Administration of rifampicin to newborn infants and children is followed by blood levels generally lower than those.found in adults for the same dose levels. In patients with impaired liver and kidney function the elimination of the antibiotic from the blood compartment is slower than in normal subjects. Rifampicin has been found to compete with bilirubin and other cholefil substances for biliary excretion, giving rise to transient and reversible increased bilirubin and BSP retention values.
A kinetic model study on the transfer constants between various body compartments has indicated that rifampicin is rapidly absorbed from the intestine and that the absorption rate increases with time. Rifampicin as such is transferred into urine at a rale 3 times higher than the rate of transfer into bile. Desacetylrifampicin, the more polar metabolic derivative of rifampicin, behaves in the opposite way since its rate of transfer into bile is 4 times higher than that into urine. The rate of biotransformation of rifampicin into desacetylrifampicin is of the same order of magnitude as that of biotransformation of the latter into a further metabolic derivative, which could be a glucuronide conjugate.
Administration of rifampicin to man is associated with proliferation of the smooth endoplasmic reticulum of the hepatocyte and with a state of induction of the drug metabolising enzyme system in the liver. As a result, drug metabolism interactions of clinical significance have been found between rifamipicin and drugs such as oral anticoagulants, oral contraceptives, oral sulphonylurea, hypoglycaemic agents, corticosteroids and digitoxin.
KeywordsRifampicin Clinical Pharmacokinetic Digitoxin Smooth Endoplasmic Reticulum Transfer Rate Constant
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- Acocella, G.; Nicolis, F.B. and Lamarina, A.: A study on the kinetics of rifampicin in man. 5th International Congress of Chemotherapy, Vienna, pp.87–93 (1967).Google Scholar
- Acocella. G.; Buniva, G.; Flauto, V. and Nicolis, F.B.: Absorption and elimination of the antibiotic rifampicin in newborns and children. Proceedings of the 6th International Congress of Chemotherapy, University of Tokyo Press 2: 755–760 (1969).Google Scholar
- Acocella, G.; Mattiussi, R. and Tenconi, L.T.: Serum concentrations and biliary excretion of bilirubin during short term treatment with rifampicin. Tijdschrift voor Gastroenterologie 16: 186–190 (1973).Google Scholar
- Acocella, G.; Mattiussi, R. and Segre, G.: Kinetic studies on rifampicin. IV. Multicompartmental analysis of serum, urine and bile concentrations of rifampicin and desacetylrifampicin in subjects treated for one week. Unpublished data (1977).Google Scholar
- Binda, G.; Domenichini. E.; Gottardi, A.; Orlandi, B.; Ortelli, E. and Pacini. B.: Rifampicin, a general view. Arzneimittel-Forschung 12a: 1907–1978 (1971).Google Scholar
- Curci, G.; Ninni, A. and Fabbroncini, V.: Ricerche sul legame farmacoproteico e sul metabolismo della rifampicina. La riforma medica 84: 197–202 (1970a).Google Scholar
- Curci, G.; Bergamini, N.; Delle Veneri, F.; Ninni, A. and Nitti, V.: Sul comportamento della cinetica della rifampicina e del tasso bilirubinemico dopo somministrazione isolata o ripetuta di differenti dosi per kg di peso corporeo nell’uomo. Archivio Monaldi per la Tisiologia e le Malattie dello Apparato respiratorio 25: 427–440 (1970b).Google Scholar
- De Gregorio, P.; La Monica, G.; Massaro, G. and Campo, G.: Clearance renale della rifampicina. Simposio sulla rifampicina, 144-B, Roma (1970).Google Scholar
- De Rautlin de La Roy, Y.; Beauchant, G., Breuil, K. and Patte, F.: Diminution du taux serique de rifampicine par le phenobarbital. La Presse medicale 79: 350 (1971).Google Scholar
- Gelber, R.H.; Gooi, H.C. and Rees, R.J.W.: The effect of rifampicin on dapsone metabolism. Proceedings of the Western Pharmacological Society 18: 330–334 (1975).Google Scholar
- Gomi, J.; Aoyagi, T.; Yamada, Y.; Mitsuno, Y. and Nanba, A.: Laboratory and clinical studies on rifampicin. Shinryo 23: 1047 (1969).Google Scholar
- Hakim, J.; Feldmann, G.; Biovin, P.; Troube, H.; Boucherot, J.; Penaud, J. and Guibot, P.: Etude comparative des activite bilirubine et paranitrophenol glucuronyl-transferasiques hepatiques. III. Effect de la rifampicine seule ou associee a la streptomycine et l’isoniazide chez l’homme. Pathologie et Biologie 21: 255–263 (1972).Google Scholar
- Hirsch, A.: Pilules endormies … La Nouvelle Presse Medicale 2: 2957 (1973).Google Scholar
- Hussels, H.:. Comparison of rifampicin serum concentrations in men following drug administration before or after breakfast. Acta tubercolosa et pneumologica belgica 60: 270–275 (1969).Google Scholar
- Keberle, H.; Kruger-Tiemer, E.; Sackmann, W.; Schmid, K. and Seydel, J.: Pharmakokinetische Untersuchungen an Rifampicin. International Congress of Chemotherapy Vienna, 4: 157–160 (1967).Google Scholar
- Krauer, B.: The pharmacokinetics of Rimactane in infants. A Symposium on Rimactane, p.35, Basel, November (1968).Google Scholar
- Kropp, R.: Rifampicin and Ovulationshemmer. Praxis der Pneumologie 28: 270 (1974).Google Scholar
- Laudano, O.M.: Efecto de la rifampicina sobre la depuracion plasmatica y excrecion biliar de la bromosulfaleina en el hombre. I1 Farmaco 27: 622–627 (1972).Google Scholar
- Menz, H.P. and Von Oldershausen, H.F.: Blood serum levels and elimination of rifampicin in acute and chronic diseases of the liver. Proceedings of the 7th International Congress of Chemotherapy, Prague, 95–97 (1971).Google Scholar
- Miano, G. and Peruzzi, G.: DeLa rifampicina: attivita antibatterica, assorbimento, diffusione ed eliminazione nell’uomo. Atti Accademia Lancisiana, Roma, 13 (suppl.): 39–61 (1969).Google Scholar
- Michot, F.; Burgi, M. and Buttner, J.: Rimactan (Rifampizin) und Antikoagulantientherapie. Schweizer Medizinische Wochenschrift 100: 583–584 (1970).Google Scholar
- Nakagawa, H. and Sunahara, S.: Glucuronidation and desacetylation in the metabolism of rifampicin in man, 23rd International Tuberculosis Conference, Mexico City (Sept. 1975).Google Scholar
- Piguet, B.; Muglioni, J.F. and Chaline, G.: Contraception orale et rifampicine. La Nouvelle Presse Medicale 4: 115–116 (1975).Google Scholar
- Radenbach, K.L.: Results of clinical studies with capreomycin, ethambutol and rifampicin in the Heckeshorn Hospital, Berlin. Scandinavian Journal of Respiratory Diseases 50(suppl. 69): 43–53 (1969).Google Scholar
- Riess, W.: The optimum dosage schedule for Rimactane. A Symposium on Rimactane, p. 36–42, Basel, November (1968).Google Scholar
- Riess, W.: Schmid, K.; Keberle, H.; Dettli, L. and Spring, P.: Pharmacokinetic studies in the field of rifamycins. Proceedings of the 6th International Congress of Chemotherapy. University of Tokyo Press 2: 905–913 (1969).Google Scholar
- Serembe, M.: Considerazioni sulla farmacocinetica della rifampicina, p. 2–7, Tavola Rotonda, Venezia (1968).Google Scholar
- Smith, R.L.: The excretory function of bile, p.213 (Chapman and Hall, London 1973).Google Scholar
- Velo, G.P. and Vettori, G.: Ricerche sull’assorbimento orale e sulla eliminazione urinaria della rifampicina. Gazzetta Internazionale di Medicina e Chirurgia 73: 2799–2804 (1968).Google Scholar