A new benzothiophene-derived antiestrogen (LY156758) when orally administered was well absorbed in rats and monkeys while approx. 20% was absorbed in dogs. In the rat the compound was subject to first-pass hepatic metabolism which led to low levels of parent drug in the systematic circulation together with a small amount as the glucuronide conjugate. In monkeys the compound occurred primarily as the glucuronide conjugate of parent drug with very little circulating free drug. The systemic bioavailability of free parent drug in plasma was 39% in rats, 17% in dogs and 5% in monkeys. Excretion of the drug in rats and dogs was primarily via the bile. Approx. 1% of the dose was excreted in the urine of rats and dogs after oral dosing. In rats, at least 50% of an oral dose was excreted in bile as the glucuronide conjugate of parent drug.

SUMMARYWe have examined the in vivo effects in chicks of intravenously injected chicken (c-) and rat (r-) calcitonin gene-related peptides (CGRP) on uptake into bone of a simultaneously administered 45Ca label. Both peptides caused transient (10 min) increases in 45Ca uptake into a variety of bone types. In dose-response experiments at 10 min, CGRP doses of 0.26-1.04 nmol/100 g body wt were found to give maximal responses. These were well developed in chicks fasted for 22 h but absent in those which were continuously fed. This contrasts with the hypercalcaemic effect of CGRP which is apparent in fed rather than fasted chicks.

1. An analytical h.p.l.c. method has been developed which permits the separation and quantification of the in vitro metabolites of 4-aminobiphenyl (4-ABP). The method employs gradient elution from a reverse phase column. 2. The major metabolite in vitro of 4-ABP in liver fractions from rat, mouse, guinea-pig, rabbit and hamster was N-hydroxy-4-aminobiphenyl. 3. The observation that liver fractions from the guinea-pig are very effective in the n-hydroxylation of 4-ABP is in excellent agreement with the 1966 report from Kiese's laboratory, showing that the N-hydroxylation of 4-ABP is an important metabolic pathway in vivo in this species. 4. The ortho-phenol, 3-hydroxy-4-aminobiphenyl was also an important metabolite in each species except guinea-pig and rabbit. 5. Hydroxylation at the 4' and 2' positions was a minor pathway in all species studied. 6. Aroclor 1254 was a potent inducer of N-hydroxylation in rat, mouse and guinea-pig but not hamster and rabbit. Phenobarbital induced N-hydroxylation in rabbit and guinea-pig but not rat, while methylcholanthrene induced in rat and guinea-pig but not rabbit.

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