Very often, an impact on the intracellular metabolism of iodothyronines and more precisely on microsomal deiodinases is evoked to explain thyroid hormone (TH) serum level alterations occurring with numerous drugs. Among them, three at least are also known to interfere with other hepatic microsomal enzymes, amiodarone (AMI), phenobarbital (PHE) and propranolol (PRO). Starting from this statement, we have examined the effects of 5 macrolides on TH serum level and on hepatic 5' type 1 deiodinase (5'DI) in vivo in rat. Rats were treated orally for eight days either with 200 mg/kg macrolides--erythromycine (ERY), troleandomycine (TRO), josamycine (JOS), midecamycine (MID) and spiramycine (SPI)--, or with AMI (45 mg/kg), PHE (50 mg/kg) or PRO (20 mg/kg), these 3 latter drugs for comparative purpose. Total T4, T3 and rT3 were determined by RIA. Hepatic 5'DI was evaluated by measuring released radioactive iodide from a reverse T3 monolabelled with 125I used substrate. Compared to control group, ERY and TRO decreased T4 (respectively by 28 and 16%) and from these two, only TRO decreased T3 (23%). With JOS, the only major modification was an increment of T3 (26%). AMI gave a typical alteration with a high T4 (130%), a low T3 (26%) and a high rT3 (376%). 5'DI was statistically inhibited by AMI (85%), JOS (49%), TRO (43%) and ERY (35%). The other drugs showed no significant effect. So, three macrolides have both altered TH serum level and 5'DI, findings which have never been reported before. The precise mechanism of this action remains unknown and the resulting effect, being far from the one observed with AMI, tends to demonstrate, for macrolides, an absence of correlation between the extent of 5'DI inhibition and TH serum profile. Besides, comparative analysis of the results observed with macrolides, AMI, PHE and PRO argues against any relationship between 5'DI and cytochrome-P450 monooxygenases.

The influence of 2 different routes of amiodarone (AMIO) administration, oral gavage (OG) and subcutaneous injection (SC), on the density of cardiac beta-adrenoceptors (Bmax), hepatic type I 5' iodothyronine deiodinase (5' DI) and thyroid hormone serum concentrations was studied. Compared with respective control values, AMIO treatment (50 mg/kg per day, 7 days) via both OG and SC routes significantly lowered Bmax (OG: 14.6 +/- 1.92 vs 18.2 +/- 1.03 fmol/mg and SC: 16.6 +/- 2.34 vs 19.1 +/- 2.05 fmol/mg) and 5' DI activity (from 409 to 85 and 340 to 47 fmol I-/mg per min, respectively). The SC route induced a fall in thyroid secretion and a generalized hypothyroidism (decreased serum FT4 and FT3, inhibition of body weight gain. The OG route did not modify thyroid secretion. These results demonstrated that the effects on cardiac beta-receptor density in the SC group might be due to the generalized hypothyroidism and that AMIO produced its specific cardiac effects only after oral route medication, suggesting that the oral route is the best choice for studying AMIO cardiac effects on beta-receptor density.