James M. Jaffe

Pharmacokinetics of Fluvastatin After Single and Multiple Doses in Normal Volunteers

The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl‐CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single‐dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple‐dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (>90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2‐ and 10‐mg doses was only 19 to 29% because of extensive first‐pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2‐ to 10‐mg dose range, as indicated by dose‐proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half‐lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40‐mg doses of [3H]fluvastatin resulted in no time‐related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first‐pass effect on fluvastatin. During repeated daily administration, plasma levels of fluvastatin reached steady state after the first dose, whereas those of total radioactivity approached steady state after 6 days. The degree of accumulation of radioactivity, unlike that of the parent drug, was inconsistent with the terminal half‐life, but instead implied a shorter effective half‐life of 32 to 36 hours. It appears that the terminal phase of the blood radioactivity profile represents a minor metabolite that is reversibiy bound to and slowly released from a specific tissue depot, and that this binding involves a finite amount of drug regardless of the dose administered. The oral and intravenous administration of [3H]fluvastatin described in the present report was safe and well tolerated.

Biological properties of the antagonist SRI 63–441 in the PAF and endotoxin models of hypotension in the rat and dog

Intravenous administration of platelet-activating factor (PAF) produces dose-dependent hypotension in several species. We have evaluated a recently developed PAF antagonist, SRI 63-441, for its ability to inhibit the hypotensive effect of PAF in the rat and dog. In the rat, 100 ng/kg PAF produced a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP), followed by a 3.2 +/- 0.7 min recovery period for MAP to return to baseline values. SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period. Dogs challenged with 1.5 micrograms/kg PAF i.v. demonstrated a 52 +/- 8% decrease in MAP that persisted for at least 15 min. The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively. In the rat model of endotoxin-induced hypotension, SRI 63-441 given 1 min after a 5 mg/kg endotoxin challenge (which produced a 52 +/- 7% decrease in MAP), reversed the systemic effects, with an ED50 of 0.18 mg/kg i.v. The ED50 for reversal 6 min after endotoxin injection was 0.01 mg/kg. These results of inhibition and reversal by SRI 63-441 strongly implicate PAF as a pivotal mediator of hypotension and shock.

Effect of altered urinarypH on tetracycline and doxycycline excretion in humans

The effect of altered urinary pH on the excretion of single doses of orally administered tetracycline hydrochloride and doxycycline hyclate was studied in humans. Alkalinization of the urine significantly enhanced the cumulative renal excretion of both tetracycline and doxycycline as compared to acidic urine treatments. Altered tubular reabsorption was assumed to have caused this effect, since tetracyclines have been shown to be more lipid soluble at their isoelectric pH (approximately the pH of the acidic urine treatment) as compared to more alkaline pHs. The renal clearance of doxycycline was significantly increased by urinary alkalinization.

Pharmacokinetics of Compound 58–112, a Potential Skeletal Muscle Relaxant, in Man

Abstract: The pharmacokinetics of 4‐[(3‐methoxyphenyl)methyl]‐2,2,6,6‐tetramethyl‐1‐oxa‐4‐aza‐2,6‐disilacyclohexane (Sandoz compound 58–112), a new chemical entity with a unique myotonolytic effect, was studied in 12 healthy male volunteers who received an oral dose of 50 or 100 mg of the 14C‐labeled drug. Serial blood and breath samples and complete urine and feces were collected for 120 hours after dosing. All samples were analyzed for total radioactivity while the blood and urine were also assayed for unchanged compound 58–112. Measurable blood radioactivity levels were observed at 0.5 hour, and peak concentrations were attained at 1 to 2 hours after dosing. The absorption of the radioactive doses was complete and appeared linear in the 50–100 mg range, as indicated by blood 14C levels that were proportional to the dose. The 50‐ and 100‐mg doses also resulted in virtually identical excretion patterns, with 95 per cent of the administered radioactivity recovered within 9 hours, almost exclusively in the urine. However, the disproportionately higher blood concentrations of unchanged compound 58–112 after the 100‐mg dose could suggest saturable presystemic metabolism in the liver. Simultaneous fitting of all data in the 100‐mg dose study to a pharmacokinetic model showed that unchanged compound 58–112 was distributed into a central and a peripheral compartment and was eliminated entirely by metabolism, the distribution and elimination half‐lives being 0.5 and 3.9 hours, respectively. The metabolite(s) was distributed into one homogeneous space, and its elimination half‐life was 0.1 hour, with a renal:fecal clearance ratio of ∼96:4.

Effect of food, fluid and dosage form on the absorption of 52–522, a potential antianxiety agent, in the dog

The absorption of 52–522 in the dog was studied by measuring blood concentrations of radioactivity after single oral doses of [14C] 52–522 in a capsule with and without water, also as a food‐drug mixture, and a solution in polyethylene glycol 400. Absorption was rapid, and its rate moderate with no significant differences in peak times among treatments. The extent of absorption was lowest after the capsulated [14C] 52–522. The solution dose gave elevated blood concentrations, that were statistically significantly different when compared with the capsules. Hence, it appears that the absorption of [14C] 52–522 is governed by the degree of dispersion of drug in the dosage form.

Enterohepatic circulation of radioactivity following an oral dose of [14C]temazepam in the rat

The enterohepatic circulation of radioactive material after administering [14C]temazepam was evaluated in three sets of male Wistar strain rats connected in pairs by bile duct‐duodenum cannulae. After a single oral dose (10 mg kg−1) to the donor rat, the excretion of radioactivity in the urine and faeces of both rats and in the bile of the recipient rat was determined. Mean total recovery of the administered radioactivity was 92·2%. Based on the amount remaining in the donor rat (gastrointestinal tract and faeces), 81·7% of the dose was absorbed by the donor. The total amount recovered from the recipient, 69·4% of original dose (85·1% of donors absorbed dose), represented the amount excreted in the donors bile. Similarly, 54·1% of the original dose (77·9% of the transferred biliary excretion from donor) was reabsorbed by the recipient, and the biliary excretion from this animal (45·9% original dose) accounted for 86·% of the amount reabsorbed.

Interspecies similarities in the disposition of 3H-dihydroergotamine following subcutaneous administration in man and rabbits

SummaryThe disposition of dihydroergotamine methanesulfonate following single subcutaneous doses was studied in man and the rabbit using radiotracer techniques.3-Dihydroergotamine was almost immediately and completely absorbed from the injection site; peak blood radioactivity levels were attained within I h of drug administration in both species. The disappearance of radioactivity from blood was biphasic, with t1/2,α and t1/2,β values of 2.9 and 16.9h, respectively, in man and 2.9 and 14.7h, respectively, in the rabbit. Apparent volumes of distribution were 18.9 Liter/kg in man and 30.4 Liter/kg in the rabbit. The excretion pattern of dihydroergotamine and its metabolites was also similar for the two species, with biliary elimination being the predominant route. At 4–5 days postdosing, 80-85%of the administered radioactivity was recovered in the feces and urine. The rabbit appears to be an adequate animal model for the study of dihydroergotamine pharmacokinetics in man.