Metabolism of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, a phenylethanolamine N-methyltransferase inhibitor. I. Disposition following administration to the rat and dog

Abstract

1. Following oral dosing of 7,8-dichloro-1,2,3,4-tetrahydro[1-¹⁴C]isoquinoline (¹⁴C-DCTQ) to rats, the plasma ¹⁴C increased steadily for 24h. In dogs, the ¹⁴C peak occurred at 40min. The concn. of unchanged drug in rats remained constant for 2h following oral administration then decreased with a t_1/2 of 18h. In the dog unchanged drug levels were highest at 20min then fell with a t_1/2 of 1·2h.

2. Intravenous administration of ¹⁴C-DCTQ to rats resulted in a biphasic fall in plasma unchanged drug levels with t_1/2 of 1.5 and 18h. In the dog after intravenous administration, plasma levels of unchanged drug fell with t_1/2 of 1·2h.

3. Binding of the drug to plasma protein in vitro was 97.9% in rat, 99.4% in dog 99.7% in human. Distribution in blood was 39.5% cellular, 59.2% protein, 1.3% free, in rat; 13.4% cellular, 86.1% protein, 0.5% free, in dog; and 7.5% cellular, 92.2% protein and 0.3% free, in human.

4. Tissues in rat that had higher concn. of ¹⁴C than blood, in decreasing order were: kidney, liver, adrenal, lung, gastro-intestinal (g.i.) tract, fat, brain (oral dosage); and lung, adrenal, brain, kidney, liver, heart, spleen, g.i. tract (intravenous dosage). Up to 80-87% of brain ¹⁴C was present as unchanged drug.

5. Rats dosed orallv with ¹⁴C-DCTQ excreted 64% of the dose of ¹⁴C in urine and 33% in faeces; after intravenous administration exretion was 58% in urine and 28% in faeces.

6. Chronic oral dosage of ¹⁴C-DCTQ to pregnant rats produced ¹⁴C concn. in the fullterm foetus, half that of maternal plasma concn.

7. Concn. of ¹⁴C in the milk of lactating rats dosed with ¹⁴C-DCTQ, averaged 87% of the plasma ¹⁴C over 5 days.