The inclusion complex formation of intravenously administered hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol-cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000-8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol-cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol-beta-cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered beta-cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl-beta-cyclodextrin after intravenous administration.

Hydroxypropyl-beta-cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 micrograms/ml. The pharmacokinetics of beta-cyclodextrin and of hydroxypropyl-beta-cyclodextrin were studied after intravenous administration to permanently cannulated rats. The pharmacokinetic behavior of both cyclodextrins was similar to that of inulin, showing rapid distribution over extracellular fluids. Elimination occurred through glomerular filtration. When a dose of 200 mg/kg beta-cyclodextrin was administered the elimination rate was decreased, probably as a result of nephrotoxicity of beta-cyclodextrin. Within 24 hr after administration most of the cyclodextrin dose was recovered unchanged in urine. After oral administration, only insignificant amounts of intact beta-cyclodextrin were absorbed from the gastrointestinal tract.

Aims Zolmitriptan (Zomig (formerly 311C90)) is a novel 5-HT 1B/1D receptor agonist developed for the acute oral treatment of migraine. A highly sensitive LCMS-MS assay has been developed which allows quantification of plasma concentrations of zolmitriptan and its active metabolite, 183C91, after therapeutic doses. Two studies using this assay method were conducted to investigate the pharmacokinetics, including absolute bioavailability, of 2.5 and 5 mg oral doses of zolmitriptan in men and women, the dose-proportionality of 2.5, 5 and 10 mg doses and the effect of food on the pharmacokinetics of a 5 mg oral dose. Methods Two randomized, balanced, open-label, 4-period crossover studies were conducted in a total of 32 healthy volunteers. The first study determined the absolute bioavailability of 2.5 and 5 mg doses of zolmitriptan and compared the pharmacokinetics in men and women. The second study examined the doseproportionality in pharmacokinetics after fasting doses of 2.5, 5 and 10 mg, and the effect of food on a 5 mg dose. Blood pressure, heart rate, ECG, clinical chemistry, haematology and adverse events were also monitored. Results The mean (s.d.) absolute oral bioavailability was 0.41 (0.14 and 0.40) 0.09 after 2.5 mg and 0.48±0.14 and 0.36±0.07 after 5 mg in women and men, respectively. Without adjustment for bodyweight, plasma concentrations of zolmitriptan, but not 183C91, were higher in women than men. Mean (±s.d.) AUC was 32.7±10.1 and 60.2±26.8 ng ml −1 h after 5 mg in men and women, respectively (95% CI for ratio 0.43-0.77). After 2.5 mg mean (±s.d.) AUC was 18.4±5.4 and 23.1±9.9 ng ml −1 h in men and women, respectively (95% CI for ratio 0.61-1.09).However, these differences were of no clinical significance. C max and AUC of oral zolmitriptan were dose-proportional and there was a 13 and 16% fall in mean zolmitriptan C max and AUC, respectively, when administered after food. Adverse effects were minor, predominantly mild and transient, and there were no clinically significant effects on ECG, blood pressure, or laboratory parameters. Conclusions At therapeutic doses zolmitriptan has good oral bioavailability in healthy volunteers and has dose-proportional pharmacokinetics that are not affected by food to any clinically relevant extent.Keywords: bioavailability, food, pharmacokinetics, zolmitriptan from 6 to 50 mg in healthy volunteers have already been Introduction described [9]. The absolute bioavailability of a single 10 mg dose is 49% [10], compared with 14% reported for Zolmitriptan (Zomig, formerly 311C90) is a new 5-hydroxytryptamine (5-HT) 1B/1D receptor agonist [1] sumatriptan 100 mg [11]. Zolmitriptan is rapidly absorbed after oral administration but as plasma profiles show multiple developed for the acute oral treatment of migraine. Clinical studies have shown it to be effective and well tolerated in peaks in some subjects, individual t max values may vary from 0.5 to 5 h [6]. Zolmitriptan is eliminated mainly by the acute treatment of migraine at doses of 2.5-25 mg, with a headache respo...

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