Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist activity and a novel pharmacological profile. Fulvestrant has been shown to significantly reduce cellular levels of the ER and progesterone receptor in both preclinical studies and in clinical trials of postmenopausal women with primary breast cancer. This paper reviews the pharmacokinetics and metabolism of fulvestrant, which support the rationale for drug delivery as a single, once-monthly intramuscular injection, and show that this agent has minimal potential to be the subject, or cause, of significant cytochrome p450-mediated drug interactions.

The intramuscular formulation of fulvestrant displays predictable kinetics and approximately 2-fold accumulation on administration once monthly. At the proposed therapeutic dosage (250 mg once monthly), plasma fulvestrant concentrations are maintained within a narrow range throughout the administration interval, thus ensuring stable systemic drug exposure during long-term treatment.

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The disposition and metabolism of meropenem were studied in rats, dogs and cynomolgus monkeys following intravenous administration of [14C]-meropenem, and also in man following intravenous infusion of meropenem. Following intravenous administration to rats and dogs, radioactive material was very rapidly and widely distributed in the tissues, with highest levels detected in the kidney and other highly perfused organs. Concentrations in all tissues decreased rapidly with time. The plasma elimination half-life of meropenem was approximately 6 min in rats, 30 min in monkeys, 45 min in dogs and 1h in man. In all species 90-100% of the dose was excreted via the urine within 24 h. Analysis of the radioactive material in urine from animal studies showed that the major components were unchanged compound (36-43%) and a metabolite corresponding to a beta-lactam ring-opened form (34-51%). In man, approximately 65% of the dose was excreted in urine as unchanged meropenem and most of the remainder as the ring-opened metabolite. As part of the preclinical safety evaluation programme of meropenem, the distribution, metabolism and excretion of [14C]-meropenem were studied in the rat, dog and cynomolgus monkey after single intravenous administration at dose levels corresponding to the lower doses used in toxicity studies. In addition, the metabolism and pharmacokinetics of meropenem in human volunteers were studied.

1. The metabolism and pharmacokinetics of 14C-meropenem were studied in five volunteers who received 0.5 g (40 microCi) of the radiolabelled drug by i.v. infusion. 2. The maximum concentration of drug in plasma was 27 +/- 2 micrograms/ml (70 microM) corresponding to 98% of plasma radioactivity at the end of a 30 min infusion. The elimination half-life for meropenem in plasma was 1 h and meropenem remained the major radioactive component up to 6 h, but represented a decreasing proportion of the plasma radioactivity with time. One metabolite (the ring-open lactam) accounted for most of the remaining plasma radioactivity. The maximum concentration of metabolite was 1 +/- 0.1 micrograms/ml and the concentration of total radioactivity decreased to 2% of the peak value by 8 h. 3. Over the 5 days of the study, urinary excretion of radioactivity accounted for 99 +/- 0.5% dose, most of which was recovered in the first 8 h. There was negligible excretion in faeces. 4. Structural confirmation of the drug-related components in urine was accomplished by h.p.l.c.-mass spectrometry. Meropenem accounted for 71 +/- 2% dose of 14C and the ring-open lactam metabolite for most of the remainder, no other metabolites were detected. 5. Meropenem was the major radioactive component in urine up to 8 h after dosing and is therefore remarkably stable to human renal dehydropeptidase (DHP-1) compared with other carbapenems in clinical use.