Resorption, Transport und Bioverfügbarkeit von Schilddrüsenhormonen

Zusammenfassung

Klassische Schilddrüsenhormone (Jodothyronine), die zu den häufigst verordneten Präparaten zählen, weisen als Pharmaka kritischer Dosierung eine geringe therapeutische Breite auf. Mittlerweile konnten die Mechanismen ihrer Resorption teilweise aufgeklärt werden – sie findet insbesondere distal des Duodenums statt. Die Bioverfügbarkeit der Jodothyronine, die an einem enterohepatischen Kreislauf teilnehmen, liegt bei ca. 70 %. Multiple Einflussfaktoren wie gleichzeitig eingenommene Medikamente, Nahrungsmittel und bestimmte Krankheitsbilder wirken sich auf ihre Resorption aus. Im Plasma zirkulieren Schilddrüsenhormone nur zu einem Bruchteil frei, der größte Anteil ist an Plasmaproteine gebunden, wobei die Bindung wiederum vielfältigen Einflüssen unterliegt. Verantwortlich für ihre intrazelluläre Akkumulation sind mindestens zehn unterschiedliche aktive und energieabhängige Transportmechanismen, die unterschiedlich im Gewebe verteilt sind. Bei bestimmten Krankheitsbildern und physiologischen Situationen ändert sich die Plasmaproteinbindung, Bei Betrachtung der Gesamthormone kann dies zu differentialdiagnostischen Schwierigkeiten führen. Veränderungen der Proteinbindung und ebenso des Membrantransports von Jodothyroninen sind insbesondere bei kritisch Kranken (NTIS) häufig. Bei der Substitutionstherapie hypothyreoter Patienten erwiesen sich unterschiedliche Handelspräparate als nicht bioäquivalent, so dass nach Umstellung der Therapie eine Kontrolle der Stoffwechsellage notwendig ist.

Summary

The frequently prescribed classical thyroid hormones (iodothyronines) are critical dose drugs with a narrow therapeutic index. Nowadays the mechanisms of their absorption, which takes place predominantly in the jejunum and ileum, have only partly been elucidated. Bioavailability of iodothyronines whose kinetics is subject to enterohepatic circulation, is about 70 %. Several factors influence their absorption including nutrients, drugs and concomitant diseases. After being absorbed only a small fraction of thyroid hormones circulates freely in plasma, whereas the greater portion is bound to plasma proteins. This binding, too, may be influenced by numerous factors; alterations by certain diseases and physiological conditions may lead to ambiguities in differential diagnosis. Intracellular accumulation of iodothyronines is accomplished by at least ten different active and energy-dependent transporters with variable tissue distribution. Particularly in critical illness (non-thyroidal illness syndrome) alterations of protein binding and membrane transport are common. In therapy of hypothyroid patients different brand-name products lack bioequivalence and thus requiring subsequent monitoring of thyroid status after treatment has been changed among different brand-name versions.

Schlüsselwörter

Schilddrüsenhormone - Hypothyreose - Bioäquivalenz

Key words

thyroid hormones - hypothyroidism - bioequivalence

Literatur

• 1 Arafah B M. Increased need for thyroxine in women with hypothyroidism during estrogen therapy.  N Engl J Med. 2001;  344 1743-1749
• 2 Benvenga S, Bartolone L, Pappalardo M A. et al . Altered Intestinal Absorption of L-Thyroxine Caused by Coffee.  Thyroid. 2008;  18 293-301
• 3 Berg J A, Mayor G H. A Study in Normal Human Volunteers to Compare the Rate and Extent of Levothyroxine Absorption from Synthroid® and Levoxine®.  J Clin Pharmacol. 1993;  33 1135-1140
• 4 Blakesley V A. Current methodology to assess bioequivalence of levothyroxine sodium products is inadequate.  Aaps J. 2005;  7 E42-46
• 5 Bolk N, Visser T J, Kalsbeek A, van Domburg R T, Berghout A. Effects of evening vs morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients.  Clin Endocrinol (Oxf). 2007;  66 43-48
• 6 Bonen A, Heynen M, Hatta H. Distribution of monocarboxylate transporters MCT1-MCT8 in rat tissues and human skeletal muscle.  Appl Physiol Nutr Metab. 2006;  31 31-39
• 7 Campbell N R, Hasinoff B B, Stalts H, Rao B, Wong N C. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism.  Ann Intern Med. 1992;  117 1010-1013
• 8 Canaris G J, Manowitz N R, Mayor G, Ridgway E C. The Colorado Thyroid Disease Prevalence Study.  Arch Intern Med. 2000;  160 526-534
• 9 Centanni M, Gargano L, Canettieri G. et al . Thyroxine in Goiter, Helicobacter pylori Infection, and Chronic Gastritis.  N Engl J Med. 2006;  354 1787-1795
• 10 Chatterji B, Borlak J. Serum proteomics of lung adenocarcinomas induced by targeted overexpression of c-raf in alveolar epithelium identifies candidate biomarkers.  Proteomics. 2007;  7 3980-3991
• 11 Christensen H N, Hess B, Riggs T R. Concentration of taurine, beta-alanine, and triiodothyronine by ascites carcinoma cells.  Cancer Res. 1954;  14 124-127
• 12 De Groot L J. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies.  Crit Care Clin. 2006;  22 57-86, vi
• 13 Dietrich J W, Boehm B O. Thyroxine in goiter, H. pylori infection, and gastritis.  N Engl J Med. 2006;  355 1177
• 14 Dietrich J W, Gieselbrecht K, Holl R W, Boehm B O. Absorption kinetics of levothyroxine is not altered by proton-pump inhibitor therapy.  Horm Metab Res. 2006;  38 57-59
• 15 Docter R, Friesema E C, van Stralen P G. et al . Expression of rat liver cell membrane transporters for thyroid hormone in Xenopus laevis oocytes.  Endocrinology. 1997;  138 1841-1846
• 16 Dumitrescu A M, Liao X H, Best T B, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene.  Am J Hum Genet. 2004;  74 168-175
• 17 Feldt-Rasmussen U, Rasmussen Å K. Thyroid Hormone Transport and Actions.  In: Krassas, GE, Kiess W Diseases of the Thyroid in Childhood and Adolescence. Vol. 11. Basel; Karger 2007: 80-103
• 18 Finke R. Diskussion bei der KBV über evtl. Einschränkung des Fachärztlichen Eigenlabors und Abschaffung der Laborgemeinschaften.  Endokrinologie Informationen. 2007;  31 9-14
• 19 Fox E L. A case of myxoedema treated by taking extract of thyroid by the mouth.  BMJ. 1892;  2 941
• 20 Friesema E C, Grueters A, Biebermann H. et al . Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation.  Lancet. 2004;  364 1435-1437
• 21 Friesema E C, Jansen J, Visser T J. Thyroid hormone transporters.  Biochem Soc Trans. 2005;  33 228-232
• 22 Glaeske G, Janhsen K. GEK Arzneimittelreport 2007. In: ErsatzKasse G-G, ed GEK-Edition. Vol. 55. Sankt Augustin; Asgard-Verlag 2007
• 23 Grasberger H, Golcher H M, Fingerhut A, Janssen O E. Loop variants of the serpin thyroxine-binding globulin: implications for hormone release upon limited proteolysis.  Biochem J. 2002;  365 311-316
• 24 Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials.  J Clin Endocrinol Metab. 2006;  91 2592-2599
• 25 Halestrap A P, Price N T. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation.  Biochem J. 1999;  343 Pt 2 281-299
• 26 Harmon S M, Seifert C F. Levothyroxine-cholestyramine interaction reemphasized.  Ann Intern Med. 1991;  115 658-659
• 27 Havrankova J, Lahaie R. Levothyroxine binding by sucralfate.  Ann Intern Med. 1992;  117 445-446
• 28 Hays M T. Thyroid hormone and the gut.  Endocrine Research. 1988;  14 203-224
• 29 Hennemann G, Docter R, Friesema E C, de Jong M, Krenning E P, Visser T J. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability.  Endocr Rev. 2001;  22 451-476
• 30 Hogness J R, Lee N D, Berg M K, Williams R H. The concentration and binding of thyroxine and triiodothyronine by rat diaphragm.  J Clin Invest. 1957;  36 803-809
• 31 Jiskra J, Limanova Z, Vanickova Z, Kocna P. IgA and IgG antigliadin, IgA anti-tissue transglutaminase and antiendomysial antibodies in patients with autoimmune thyroid diseases and their relationship to thyroidal replacement therapy.  Physiol Res. 2003;  52 79-88
• 32 Krehan A, Dittmar M, Hoppen A, Lichtwald K, Kahaly G J. Randomisierte, doppelblinde Crossover-Studie zur Bioverfügbarkeit von Levothyroxin.  Medizinische Klinik. 2002;  97 522-527
• 33 Laji K, Rhidha B, John R, Lazarus J, Davies J S. Abnormal serum free thyroid hormone levels due to heparin administration.  Qjm. 2001;  94 471-473
• 34 Liel Y, Harman-Boehm I, Shany S. Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients.  J Clin Endocrinol Metab. 1996;  81 857-859
• 35 Liel Y, Sperber A D, Shany S. Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide.  Am J Med. 1994;  97 363-365
• 36 Meier C, Ristic Z, Klauser S, Verrey F. Activation of system L heterodimeric amino acid exchangers by intracellular substrates.  Embo J. 2002;  21 580-589
• 37 Oppenheimer J H, Bernstein G, Hasen J. Estimation of Rapidly Exchangeable Cellular Thyroxine from the Plasma Disappearance Curves of Simultaneously Administered Thyroxine-131I and Albumin 125I.  Journal of Clinical Investigation. 1967;  46 762-777
• 38 Peeters R P, van der Geyten S, Wouters P J. et al . Tissue thyroid hormone levels in critical illness.  J Clin Endocrinol Metab. 2005;  90 6498-6507
• 39 Rajatanavin R, Liberman C, Lawrence G D, D’Arcangues C M, Young R A, Emerson C H. Euthyroid hyperthyroxinemia and thyroxine-binding prealbumin excess in islet cell carcinoma.  J Clin Endocrinol Metab. 1985;  61 17-21
• 40 Schifferdecker E, Hering S, Bohm B O. et al . Thyroid hormone binding inhibition in critically ill patients – who is the inhibitor?.  Exp Clin Endocrinol. 1990;  95 267-270
• 41 Singh N, Singh P N, Hershman J M. Effect of calcium carbonate on the absorption of levothyroxine.  JAMA. 2000;  283 2822-2825
• 42 Sperber A D, Liel Y. Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminum hydroxide.  Arch Intern Med. 1992;  152 183-184
• 43 Stockigt J R, Lim C F, Barlow J W. et al . Interaction of furosemide with serum thyroxine-binding sites: in vivo and in vitro studies and comparison with other inhibitors.  J Clin Endocrinol Metab. 1985;  60 1025-1031
• 44 Surks M I, Sievert R. Drugs and thyroid function.  N Engl J Med. 1995;  333 1688-1694
• 45 Van den Berghe G. Dynamic neuroendocrine responses to critical illness.  Front Neuroendocrinol. 2002;  23 370-391
• 46 Wang R, Nelson J C, Wilcox R B. Salsalate and salicylate binding to and their displacement of thyroxine from thyroxine-binding globulin, transthyrin, and albumin.  Thyroid. 1999;  9 359-364