Clotrimazole (Bay b 5097): In Vitro and Clinical Pharmacological Studies

Abstract

Clotrimazole (Bay b 5097) is a new synthetic antifungal drug with in vitro activity against Candida spp., Torulopsis glabrata, and Saccharomyces spp. Pharmacological studies in man after the oral administration of 1.5 and 3 g of clotrimazole produced mean peak concentrations in the serum of 1.16 and 1.29 mg/ml, respectively, 2 hr after administration. In six patients taking 1.5 g of clotrimazole every 6 hr, there was a progressive decline in the serum concentrations after administration of a dose on days 1, 4, and 8. Nine other patients begun on a similar schedule manifested gastrointestinal symptoms attributed to the clotrimazole and were unable to complete the study. Concentrations of active drug in the urine were less than 1 N of the administered dose.Systemic fungal infections contribute significantly to the morbidity and mortality of patients with hematological malignancies (1, 7) and of transplant patients receiving immunosuppressive therapy (13,17,20 (Fig. 1). Several reports indicate that this agent has broad in vitro antifungal activity against both pathogenic yeasts and filamentous fungi (10,12,16,23 phosphatase. There was an interval of at least 48 hr between studies in the same individuals, and all studies were done after an overnight fast. Single-dose studies were performed in seven normal volunteers and one cancer patient with doses of 1.5 and 3 g of clotrimazole. Serum specimens were collected immediately prior to each study and at 1, 2, 3, 4, and 6 hr after administration of the drug. Urine specimens were collected immediately prior to each study and for 6 hr after drug administration.To determine the effect of multiple dosing on serum levels, 15 cancer patients being treated for their disease in protected-environment units (2) were begun on clotrimazole, 1.5 g every 6 hr for 8 days. All of these patients were receiving prophylactic oral nonabsorbable antibacterial antibiotics (3) but no other antifungal agents during the period of study. The studies 423 Vol. 2,No. 6

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

“…Pharmacokinetic information on CLT in humans indicates that, in healthy subjects after a single oral dose of 1 g CLT (Ϸ15 mg͞kg body weight), plasma levels reach mean peak concentrations of about 2 M within 2-4 hr of administration (15,16). Similar and even higher CLT levels have been found by others after oral administration of comparable doses (12,17). Most of CLT in plasma is bound to lipoproteins, 4% is bound to albumin, and less than 1% appears to be free (15).…”

Overview of medically important antifungal azole derivatives

“…Pharmacokinetic studies in humans demonstrated a progressive decline over several days in the serum concentrations of clotrimazole after oral administration; these data supported the hypothesis of liver enzyme induction by the drug (43,141). Unacceptable side effects include high incidences of gastrointestinal disturbances following oral administration of clotrimazole (43,47,339) and alterations in hepatic and adrenal functions (300 (181).…”

“…Clotrimazole is more active than griseofulvin and nystatin against dermatophytes as well. Its broad spectrum and potent activity have been confirmed in many studies (26,43,220,264,345). Very short contact time is required for clotrimazole to effect its antifungal activity (246), and as with the other imidazoles, the suggested mode of action appears to be disturbance of the fungal cell membrane.…”

Inhibition and killing of Candida albicans in vitro by five imidazoles in clinical use

“…We found in the spectrophotometric assay of IC1/2 that all of the drugs were active, even compared with concentrations achieved in serum after systemic administration (4,5,7,11,12,14,19). Their activity was very similar, with clotrimazole slightly less active.…”