Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans

The pharmacokinetics of a single oral dose of the neuroleptic drug zuclopenthixol (10 or 6 mg) was studied in 6 extensive and 6 poor metabolizers of debrisoquine. The peak plasma concentrations of zuclopenthixol did not differ between the phenotypes, whereas the plasma elimination half-life was significantly longer in poor than in extensive metabolizers (29.9 +/- 6.6 vs 17.6 +/- 6.9 h). Accordingly, the total oral plasma clearance was lower in poor than in extensive metabolizers (0.78 +/- 0.27 vs 2.12 +/- 0.65 1/h/kg). Ten of the volunteers had previously participated in a similar study in which the kinetics of perphenazine, another neuroleptic drug, were studied in poor and in extensive metabolizers of debrisoquine. There was a significant correlation between the oral clearance of perphenazine and that of zuclopenthixol among these 10 subjects. The study indicates that the disposition of zuclopenthixol, as well as that of perphenazine, is related to the genetically determined capacity to hydroxylate debrisoquine. The significance of this polymorphism for the clinical use of neuroleptics is discussed.     

Almitrine bismesylate disposition in the human digestive tract

Summary The absorption of almitrine from the upper gastrointestinal tract has been evaluated in 6 healthy volunteers by an intubation technique. Almitrine bismesylate dissolved in malic acid was introduced into the stomach after homogenization with a meal containing the marker¹⁴C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was infused into the second part of duodenum throughout the experiment. Samples of the luminal content were collected every 15 min for four hours from the stomach and at the ligament of Treitz. Blood was also collected.Almitrine was neither absorbed from nor metabolized in the stomach. About 37% of the quantity of drug emptied from the stomach was absorbed from the duodenum. Almitrine was detected in plasma 50 min after ingestion of the meal and its plasma concentration-time profile reflected the cumulative gastric emptying rate. The metabolite tetrahydroxy almitrine was found in intestinal samples as soon as unchanged drug was detected in plasma. The intraluminal rate of formation of the metabolite increased with time.The results suggest hepatic metabolism of almitrine followed by rapid excretion of the metabolite in the bile.     

The effect of age on the pharmacokinetics of the opioid antagonist nalmefene

1 The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1  mg ( n =18 young; n =11 elderly) or 2  mg ( n =8 young; n =15 elderly) intravenous bolus dose of nalmefene.
2 Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1  l  kg⁻¹ for 1  mg dose). The elderly volunteers also had a significantly shorter distributional half-life ( t1/2λ1 ) than young volunteers (0.7±0.7 vs 1.3±0.8  h for 1  mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution.
3 Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.     

The behaviorally active peptide ACTH 4-10: Measurement in plasma and pharmacokinetics in man

Summary A specific radioimmunoassay for the quantitative measurement of ACTH 4-10 and a procedure for its extraction from plasma have been developed.Its pharmacokinetics was studied in eight healthy male volunteers given ACTH 4-10 125 µg/kg body weight as a bolus i.v. injection, by infusion and intranasally. Following the i.v. bolus, plasma levels rapidly declined biexponentially, with half-lives of 0.39±0.05 min for the -phase and 3.84 ± 1.5 min for the -phase (mean±SD). The constant rate i.v. infusion yielded steady-state levels between 0.74 and 5.06 ng/ml plasma. Administered as intranasal spray, absorption of intact ACTH 4-10 was low and variable (maximal bioavailability 7.6%).The results are discussed in relation to the dose-dependent effects of ACTH 4-10 on the auditory evoked potential.     

Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects

Summary The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 g and 6 g has been investigated in 6 healthy subjects on a low carnitine diet.Carnitine was more rapidly eliminated from plasma after the higher dose. Comparing the 2-g and 6-g doses, the t_1/2 of the elimination phase () was 6.5 h vs 3.9 h, the elimination constant was 0.40 vs 0.50 h^–1 and the plasma carnitine clearance was 5.4 vs 6.11 × h^–1 (p<0.025), thus showing dose-related elimination.Saturable kinetics was not found in the range of doses given. The apparent volumes of distribution after the two doses were not significantly different and they were of the same order as the total body water. Urinary recoveries after the 2-g and 6-g doses were 70% and 82% during the first 24 h, respectively.Following the two oral dosing, there was no significant difference in AUCs of plasma carnitine. Urinary recoveries were 8% and 4% for the 2-g and 6-g doses during the first 24 h. The oral bioavailability of the 2-g dose was 16% and of the 6 h dose 5%. The results suggest that the mucosal absorption of carnitine is already saturated at the 2-g dose.     

Endocrinology: Comparative pharmacokinetics of two urinary human follicle stimulating hormone preparations in healthy female and male volunteers

These studies were designed to compare the pharmacokinetic characteristicsof a very highly purified urinary human follicle stimulatinghormone (FSH-HP) preparation (sp. act. 9000 IU FSH/mg of protein),Metrodin HP^®, with a standard urinary FSH preparation Metrodin^®(FSH). The two preparations were administered in a balanced,random-order, cross-over sequence as single doses of 150IU,separated by 1 week of washout to 12 female volunteers by i.v.injection and to 12 male volunteers by i.m. and s.c. routes.FSH concentrations were measured by immunoradiometric assayand by an in-vitro rat granulosa cell aromatase bioassay. Afteran i.v. bolus, the pharmacokinetics of the two FSH preparationswere identical. Total clearance was 0.5 and 0.15 1/h respectivelyfor immunoassay and bioassay data. Immunoassay showed that thetwo preparations were similar for renal clearance (0.1 1/h),volumes of distribution at steady state (9 1), distributionand terminal half-lives (2 and 17 h, respectively). After parenteraladministrations, the absorption half-life of FSH was 3 h andthe apparent terminal half-life was 1.5 days. Both preparationshad relative bio-availabilities close to 100% for i.m. and s.c.administrations. Immunopurification, which results in a veryhighly purified FSH-HP, does not modify the pharmacokineticproperties of FSH. This study also confirmed that s.c. and i.m.doses of FSH-HP are equivalent from the pharmacokinetic andpharmacodynamic points of view.     

Pharmacokinetics of a novel oral slow-release form of misoprostol

BACKGROUND: The pharmacokinetics of a novel slow-release (SR) misoprostol was studied and compared to conventional misoprostol. METHODS: Thirty-one women, pregnant between 8 and 12 weeks, requesting surgical abortion were randomly allocated to receive orally 400 microg conventional misoprostol, 400 microg SR misoprostol or 800 microg SR misoprostol. Venous blood samples were taken at 0, 30, 60, 120, 240 and 360 min after the administration of misoprostol. Misoprostol acid (MPA) was determined in serum samples using liquid chromatography/tandem mass spectrometry. RESULTS: Serum peak concentration (Cmax) was highest for conventional oral misoprostol. The time to peak concentration (Tmax) was similar for all groups. The area under the curve up to 360 min was similar for conventional and for 800 microg SR misoprostol and significantly greater for these groups compared to 400 microg SR misoprostol (P = 0.013). CONCLUSION: The new SR form of misoprostol demonstrated lower peak levels but longer-lasting elevation in plasma levels compared to conventional oral misoprostol. The AUC for 800 microg SR misoprostol was similar to that of 400 microg of conventional oral misoprostol. SR misoprostol may offer an alternative to repeated administration of oral misoprostol or to vaginal administration.     

Pharmacokinetics of tolfenamic acid in patients with cirrhosis of the liver

Summary Six patients with alcoholic cirrhosis of the liver received 100 mg tolfenamic acid p.o. and i.v. The disposition of tolfenamic acid could be described by a two-compartment open body model, with a mean central compartment volume of 8.71, and a -phase volume of 251. The elimination rate constant k_e averaged 1.13 h^–1 and the half-life of the -phase was 1.73 h; the mean total plasma clearance was 159 ml/min. These pharmacokinetic parameters differed only slightly from those in two groups of healthy volunteers studied previously; k_e was significantly reduced by about 30% in the patients but none of the other parameters differed significantly. There was good correlation between individual elimination rate constants or plasma clearances with the liver function tests, serum albumin and P-coagulation factors. Oral absorption was good and bioavailability of about 100% was shown by comparison of the areas under the plasma concentration — time curves after i.v. and p.o. administration. Metabolism was qualitatively and quantitatively very similar to previous observations in healthy volunteers. There seems no reason to reduce the dose of tolfenamic acid in patients with compensated alcoholic cirrhosis.     

Intravenous and intramuscular pharmacokinetics of recombinant leukocyte a interferon

Summary Interferon is currently being evaluated for the treatment of disseminated cancer and viral diseases. Alpha interferons have shown to be effective in the treatment of a number of malignancies. Recombinant leukocyte A interferon (rIFN-A) is an alpha interferon produced by recombinant DNA techniques. A kinetic evaluation of rIFN-A following intravenous and intramuscular administration has not been adequately defined. The present study was designed to evaluate the kinetics of rIFN-A following intravenous and intramuscular administration of 3, 9 or 18×10⁶ units to patients with disseminated cancer.A preliminary report of this study was presented at the meeting of the American Society for Clinical Pharmacology and Therapeutics in San Diego, March 1983 (1).