Bioavailability of intranasal formulations of dihydroergotamine

Objective: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. Methods: Two intranasal formulations of DHEM in combination with randomly methylated β-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray ( =two puffs of 100 μl); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray ( =four puffs of 125 μl); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. Results: No statistically significant differences were found in maximum plasma concentration (C_max), time to reach C_max (t_max), area under plasma concentration–time curve (AUC_0–8 h), Frel_(t=8 h) and C_max/ AUC_(t=8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. Conclusion: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers. Received: 12 February 1999 / Accepted in revised form: 23 August 1999     

Capacity-limited renal glucuronidation of probenecid by humans A pilotVmax-finding study

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, thet _1/2 increased from 3 to 6 h. TheC _max was 14g/ml with a dosage of 250 mg, 31g/ml with 500 mg, 70g/ml with 1,000 mg and 120g/ml with 1,500 mg. Thet _max remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6–0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34–59%). The protein binding of probenecid glucuronidein vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate-time profile of probenecid glucuronide shows a plateau value of approximately 700g/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects itsV _max of formation.     

Disposition of quinine in rats with induced renal failure

Aetiologically different models of experimental acute renal failure were induced in rats by the administration of glycerol, mercuric chloride and gentamicin, respectively, to different groups. Quinine levels in plasma and urine of the rats with induced renal failure were determined and pharmacokinetic parameters (eliminationt _1/2, CL _p ,V, CL_R AUC_0–) of the drug were derived and compared with values obtained from control rats following intraperitoneal administration of a 10 mg/kg body-weight dose of quinine. Results showed that each of the three compounds caused an up to 25-fold increase in the plasma levels of the drug and a marked decrease in the levels of the metabolite 3-hydroxyquinine. All the pharmacokinetic parameters determined for the rats with renal impairment were markedly different when compared to control. The high plasma quinine levels observed in the rats with renal failure could be largely due to the marked decrease inV and reduced metabolism. Also, in the rats with renal impairment, no correlation was observed between the increased plasma urea levels and plasma quinine levels or disposition of the drug. The results of the study suggest that quinine should be used with caution in patients with renal impairment. The plasma urea levels, as a measure of renal function, might not provide a suitable index for determining quinine dosage.     

Anticonvulsant and proconvulsant properties of viloxazine hydrochloride: Pharmacological and pharmacokinetic studies in rodents and the epileptic baboon

Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED₅₀ for abolition of tonic extension was 9 mg/kg^-1 after 30-min pretreatment (mouse) rising to 30 mg/kg^-1 after 60 min (mouse and rat). Comparable ED₅₀ values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED₅₀ for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg^-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5–1 g/ml^-1. In the baboon, significant protection against photomyoclonic responses is observed 1–2 h after viloxazine (2.6 mg/kg^-1 IV), during which period the plasma concentration was again 0.5–1 g/ml^-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg^-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed.     

Plasma concentrations of valproate during maintenance therapy in epileptic children

Summary A total of 20 children with various types of epilepsy were treated with valproate, 11 with monotherapy and 9 with valproate in combination with phenobarbitone, phenytoin, or carbamazepine. Valproate was given either every 8 or 12 h. At least two different dose levels were tried in each patient. The pharmacokinetics of valproate during the interval between doses was determined using a gas chromatographic technique. The clinical effect of the treatment was assessed by interviewing the parents.The plasma concentrations showed considerable fluctuation during the intervals between doses. The mean increase from pre-administration to peak level was 82% when the dose interval was 12 h, and 62% when it was 8 h. The mean plasma half-life of valproate, using a one-compartment model, was 10.9±1.3 h (mean±SD). The plasma half-life of valproate was decreased when the drug was combined with the other anti-epileptics. The calculated area under the concentration versus time curve was linearly related to dose, both in a single patient on four dose levels and when different patients were compared. The clinical effect of valproate monotherapy was best in patients with absences, usually good in myoclonus and less favourable in other types of epilepsy. For children with absences, the optimal dose range of valproate was between 20 and 40 mg/kg/24 h. In comparison, the myoclonic types of epilepsy needed a slightly higher dose level, between 30 and 60 mg/kg/24 h. In the latter group a therapeutic window seems to exist, since patients below and above the suggested dose levels were not well-controlled. Therapeutic monitoring of valproate does not appear meaningful when the drug is used as monotherapy. However, in combination therapy, determination of the plasma levels of all anti-convulsants used may be helpful. The large fluctuations of valproate during a dose interval must be taken into consideration when the clinical effects are analysed.Supported by the Swedish Medical Research Council (Project No. 522), Stiftelsen Margarethahemmet, and Sällskapet Barnavård     

Clinical effects and plasma levels of Δ9-Tetrahydrocannabinol (Δ9-THC) in heavy and light users of cannabis

⁹-Tetrahydrocannabinol (⁹-THC) was administered in a crossover design by smoking and IV injection to groups of heavy and light users of marihuana. Plasma concentrations of ⁹-THC were similar for the groups after IV injection of 5.0 mg ⁹-THC, but the AUC_{0–240 min} showed a trend towards lower values for the heavy user group. To achieve a maximum desired high, both groups smoked similar amounts (about 13 mg) of ⁹-THC. Heavy users tended to have higher plasma levels than light users. The systemic availability of smoked ⁹-THC was significantly higher for the heavy users (heavy users 23±16% vs 10±7% for light users). These results also indicate that heavy cannabis users smoke more efficiently than casual smokers.Both light and heavy users showed more clinical effect following IV administration than after smoking. The response of the heavy users, both with respect to effect on heart and high, was quite comparable to that of light users.The present study does not suggest that tolerance readily develops in heavy users.     

Effect of age on levels of diazepam in plasma and brain of rats

Summary The pharmacokinetics and distribution in brain and cerebellum of diazepam after a single dose were studied in middle aged (6 months) and old (18 months) rats. Following the single intravenous bolus of 5 mg/kg diazepam was eliminated more slowly in old rats (T _1/2()=3.1h) than in middle aged rats (1.4 h). This was due to an increase in the apparent volume of distribution Vd from 11.0 l/kg (control rats) to 29.5l/kg. Concentrations of diazepam in brain and cerebellum were in the same range (0.5–1.1 ng/mg) in both groups after this dose. We conclude that the distribution of diazepam is age-dependent which might be due to an altered body composition.     

Pharmacokinetics of ascorbic acid in man

Summary The pharmacokinetic characteristics of ascorbic acid have been investigated in normal adult volunteers, using a two-compartment open model. After oral administration in a normal gelatine capsule the bioavailability of ascorbic acid was 69%. It was 98% when a sustained-release preparation was given in an identical capsule. During daily oral intake of ascorbic acid 1 g in the sustained-release form blood levels reached the equilibrium state within 3 days. Daily doses of ascorbic acid 1 g resulted in tissue saturation in 7 days, with a profound change in the pharmacokinetics of the vitamin. The binding of ascorbic acid to plasma proteins was low (24%). Its significance for the pharmacokinetic behaviour of the drug is discussed.     

Pharmacokinetics of spironolactone in man

Summary Five healthy male volunteers received 500 mg Aldactone^® orally together with 100 Ci ³H-20-21-spironolactone; one elderly patient received 1 mCi ³H-spironolactone without additional cold drug. For 6 days the disposition kinetics of the drug were studied in plasma, urine and feces. The tritium concentrations in plasma reached a peak between 25–40 min after administration amounting to 2–3% of the dose/1. Up to the 12th h, they fell rapidly and showed a monoexponential decline (t _1/2 : 2.57±0.27 days) between the 36th and 96th h. Later, a striking increase in the speed of elimination of radioactivity from plasma (t _1/2 : 1.66±0.21 days) was observed. The biological half-life of labeled material in plasma was longer than that of fluorigenic compounds. 47–57% of the dose were excreted in urine and the remaining amount culd be detected in feces (total recovery 90%). The half-life of the urinary excretion rate was distinctly shorter (t _1/2 : 0.9±0.11 days) than that of total radioactivity in plasma. This, together with an observed increase of the polar fraction in urine from 35 up to 85%, which was accompanied by a decrease in plasma from 55 to 35%, suggests either tubular reabsorption or enterohepatic recirculation of lipophilic compounds. TLC-separation of the lipophilic fraction in urine revealed two previously unknown compounds of which the main congener was identified as 3-(3-oxo-7-methylsulfonyl-6, 17-dihydroxy-4-androsten-17-yl) propionic acid -lactone, as well as canrenone and the metabolites which have already been described (Karim and Brown, 1972; Karim et al., 1975). This metabolite represents the main lipophilic degradation product in urine within the first hours, whereas the 6-OH-7-methylsulfinylspirolactone leveled off and seemed to be an endexcretion product. For further characterisation, the polar fraction was subjected to acidic hydrolysis. The known metabolic pathways of spironolactone degradation are discussed.The paper includes parts of the thesis of G. Luszpinski     

Effect of phenobarbital pretreatment on in vitro enzyme kinetics and in vivo biotransformation of benzene in the rat

Phenobarbital pretreatment (50 mg/kg/day for 3 days orally) of male Wistar rats increased V _max of benzene in vitro hepatic microsomal biotransformation about 6-fold without changing K _m . However, benzene blood levels after oral, intraperitoneal, or subcutaneous benzene administration (3–3.5 mmoles/kg) were not influenced by phenobarbital pretreatment. The phenol blood levels after oral or intraperitoneal benzene were increased by phenobarbital pretreatment, but less than expected from in vitro data and only 3 h after benzene administration. Phenol elimination in urine after subcutaneous benzene was not affected by phenobarbital. After oral or intraperitoneal benzene administration, phenol urine excretion closely followed the levels of phenol in blood, i.e., rate of phenol urine excretion was significantly, but shortly increased, and the cumulative urine excretion of phenol increased very little or remained unchanged. Differences between the in vitro and in vivo observations of the effect of phenolbarbital on benzene biotransformation may partly be explained by distribution of benzene, which apparently limited benzene availability for biotransformation (V _d =5.5) and caused rapid decrease of benzene concentrations in blood. Conditions for enzyme activity may have been substantially different in vitro vs. in vivo: in vitro concentrations of benzene were at least by an order of magnitude higher than phenol concentrations, while in vivo, an opposite relation prevailed making a competition for microsomal monooxygenase possible. Cofactor availability may be another rate-limiting step or factor of in vivo benzene biotransformation, as benzene ring hydroxylation requires high energy. The rate of in vitro hepatic microsomal benzene biotransformation proved to be of limited value when predicting benzene quantitative biotransformation in vivo in contradistinction to various substrates where the in vitro and in vivo biotransformation data are in good agreement