Pharmacokinetics and pharmacodynamics of cetirizine in infants and toddlers.

The pharmacokinetics of the second generation H1-receptor antagonist cetirizine were studied in 15 infants and toddlers (mean +/- SD age, 12.3 +/- 5.4 months) who were treated with a single 0.25 mg/kg dose of cetirizine solution. The infants and toddlers were hospitalized for recurrent respiratory infections or other hypersensitivity-related diseases. Blood samples were collected at 1/2, 1, 11/2, 2, 4, 6, 8, 12, and 24 hours, and a 24-hour urine sample was obtained. A peak plasma level of 390 +/- 135 ng/ml was observed after 2.0 +/- 1.3 hours. The elimination half-life was 3.1 +/- 1.8 hours, the apparent oral body clearance was 2.13 +/- 1.15 ml/min/kg, and the apparent volume of distribution was 0.44 +/- 0.19 L/kg. The excretion of unchanged cetirizine in six complete urinary collections was 62.7% +/- 13.2% of the administered dose. An additional pharmacodynamic study (inhibition of the histamine-induced wheal and flare) was performed in 10 of these infants and toddlers, after the intake of 0.25 mg/kg cetirizine twice a day for at least 4 days. A 90% +/- 12% inhibition of the wheal and a 87% +/- 17% inhibition of the flare were still observed 12 hours after the last intake. The duration of the H1-inhibition by cetirizine at the cutaneous level is thus longer in infants and toddlers than could be inferred from its pharmacokinetics; the level of inhibition at 12 hours was the same as in older age groups.

Pharmacodynamic activity of lipoprotein lipase and hepatic lipase, and pharmacokinetic parameters measured in normolipidaemic subjects receiving ciprofibrate (100 or 200 mg/day) or micronised fenofibrate (200 mg/day) therapy for 23 days.

The activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were investigated after 23 days of ciprofibrate (100 mg or 200 mg) therapy or fenofibrate (200 mg) therapy. In a double-blind, double-placebo, cross-over study, three groups of six healthy volunteers received either 100 mg ciprofibrate/day followed by 200 mg fenofibrate 'high bioavailability' (HB)/day, or vice versa (group A), 200 mg ciprofibrate HB/day followed by 200 mg fenofibrate HB/day, or vice versa (group B), or 100 mg ciprofibrate/day followed by 200 mg ciprofibrate/day, or vice versa (group C). Fasting plasma lipid levels and safety parameters were evaluated before and after treatment. One hundred milligrams ciprofibrate/day therapy was found to be approximately as effective as 200 mg fenofibrate HB/day therapy in altering the lipid profile. The highest activation of LPL was obtained after treatment with 200 mg ciprofibrate/day. A modest, but statistically significant, increase in HL activity was found after 100 or 200 mg ciprofibrate treatment. Investigation of the pharmacokinetics of ciprofibrate and fenofibric acid revealed a shorter time to reach peak plasma levels, but a longer elimination half life for the ciprofibrate preparations in comparison with fenofibrate. A dose of 200 mg ciprofibrate/day is more effective than 100 mg ciprofibrate/day at increasing LPL and HL activity; however, 200 mg ciprofibrate/day is also associated with a potential detrimental change in safety parameters. Two hundred milligrams fenofibrate HB/day therapy may represent an alternative therapy to 100 mg ciprofibrate/day for hyperlipidaemic patients.

Lack of Clinically Relevant Interaction of Cetirizine on Theophylline Disposition in Healthy Subjects: A Placebo-Controlled Study.

The possible interaction of a steady-state cetirizine treatment, a nonsedating H(1) antihistamine, on the disposition of a single I.V. infusion of theophylline was studied in six healthy male volunteers. As a corollary, it was checked whether this single theophylline administration modified the steady-state condition of cetirizine. A three-period, two-treatment, crossover design was used, each period being separated by a washout of 1 week. Each period consisted of the oral administration of 10 mg cetirizine or of a matching placebo every 12 h for 3½ days, the last intake being followed, 1 hour later, by a single 1-h I.V. infusion of 240 mg theophylline or of placebo. The sequence of treatments (A = cetirizine + theophylline placebo, B = cetirizine placebo + theophylline, C = cetirizine + theophylline) was alloted by a double Latin-square randomization. The repeated administration of cetirizine induced a 3% decrease of the urinary elimination of unchanged theophylline; the total body clearance of theophylline was marginally (+5%) and not significantly modified. Theophylline slightly lengthened the elimination half-life of cetirizine (from 8.3 to 9.9 h), without modification of its apparent total body clearance; the half-life of cetirizine remaining in the normal range. These subtle modifications are not clinically relevant and it may, thus, be considered that cetirizine exerts no pertinent interaction on theophylline disposition.

D-propoxyphene and norpropoxyphene kinetics after the oral administration of D-propoxyphene: a new approach to liver function?

In an attempt to design a liver function test which takes into account both portal-systemic shunting and hepatocellular dysfunction, we investigated a group of patients with cirrhosis with or without surgical porta-caval shunt for d-propoxyphene and its major metabolite, norpropoxyphene kinetics. A small dose of d-propoxyphene (0.7 mg/kg body weight) was given orally to seven normal subjects, 15 patients with cirrhosis and seven patients with cirrhosis and surgical portacaval shunt. D-propoxyphene and norpropoxyphene areas under the plasma concentration-time from 0 to 4-h (AUC) were determined by the trapezoidal method. As d-propoxyphene is a high extraction drug and since the production of norpropoxyphene should reflect the amount of d-propoxyphene available to the hepatocytes, we tested the hypothesis that norpropoxyphene/d-propoxyphene AUC ratios should reflect both the degree of portal-systemic shunting and the severity of hepatocyte dysfunction. Norpropoxyphene/d-propoxyphene AUC ratios were significantly lower in patients with cirrhosis (mean +/- S.D.: 0.92 +/- 0.59) than in controls (2.51 +/- 0.45) and also significantly lower in patients with cirrhosis and a surgical shunt (0.53 +/- 0.23) than in patients with cirrhosis but without surgical shunt (1.10 +/- 0.63). Moreover, there was an overall statistically significant correlation between norpropoxyphene/d-propoxyphene AUC ratios and branched to aromatic amino acids ratios (rs = 0.91) and fasting venous NH4 (rs = -0.63). On the other hand, there was only a weak correlation between norpropoxyphene/d-propoxyphene AUC ratios and the 14C-aminopyrine breath test (rs = 0.43). These data suggest that the norpropoxyphene/d-propoxyphene AUC ratio reflects both shunting and reduced hepatocellular function.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of cimetidine on the pharmacokinetics of single oral doses of alfuzosin.

Alfuzosin is a new alpha 1-adrenoceptor antagonist particularly effective in the symptomatic treatment of benign prostatic hypertrophy (BPH). The elimination of alfuzosin being almost entirely metabolic, the potential pharmacokinetic interaction with cimetidine (H2-receptor antagonist) was investigated in 10 healthy young subjects. Pharmacokinetics of alfuzosin were appraised as a 5 mg oral dose before, after one day and after 20 days of cimetidine (1 g/d) administration. An inhibition of the hepatic mixed function oxidase system by cimetidine was established by the oral antipyrine clearance test. Under these conditions, alfuzosin pharmacokinetics were only marginally affected by concomitant cimetidine administration. Surprisingly, a significantly shorter elimination half-life was found after 20 days on cimetidine (from 5.1 +/- 0.4 h to 4.4 +/- 0.5 h). This fact must be attributed to the large inter-individual variation in pharmacokinetic parameters reported for alfuzosin. Cmax and AUC increased up to 20% after cimetidine but without statistical significance. No side-effects on the association cimetidine-alfuzosin were reported. In conclusion, there is a lack of pharmacokinetic interaction on cimetidine-alfuzosin co-administration.

Single-dose pharmacokinetics of cetirizine in patients with chronic liver disease.

The pharmacokinetics of the H1-receptor antagonist cetirizine were studied from 0 to 72 hours after a single dose of 20 mg in 5 patients with chronic hepatocellular liver disease (group A), in 5 patients with chronic cholestatic liver disease (group B), and in 16 healthy volunteers. The renal function of patients and volunteers was normal (creatinine clearance > or = 70 mL/min). Cetirizine pharmacokinetics were similar in the two groups of patients. The elimination t1/2 was prolonged in patients (mean +/- standard deviation; group A: 14.32 +/- 2.30 hours; group B: 13.86 +/- 3.14 hours) in comparison with the values observed in volunteers (9.42 +/- 2.4 hours). A reduced apparent oral body clearance also was observed in patients (group A: .48 +/- .23 mL/min/kg; group B: .41 +/- .09 mL/min/kg) in comparison with volunteers (.74 +/- .19 mL/min/kg). No differences were observed in the mean cumulative urinary excretion between patients (group A: 69 +/- 15%; group B: 69 +/- 13%) and volunteers (70.7 +/- 7.8%).

Effects of simvastatin and pravastatin on 6 beta-hydroxycortisol excretion, a potential marker of cytochrome P-450 3A.

The influence of two inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, simvastatin and pravastatin, on the level of urinary 6 beta-hydroxycortisol/17-hydroxycorticosteroids (6 beta-OHC/17-OHCS) ratio was determined in two groups of normolipidemic Caucasian subjects (n = 18 and n = 14, respectively). The 6 beta-OHC/17-OHCS ratio increased significantly after simvastatin administration (20 mg day-1 for 17 days) (P = 0.0125) whereas no modification was observed after pravastatin administration (20 mg day-1 during 17 days). As the level of 6 beta-OHC/17-OHCS ratio is a function of cytochrome P-450 3A activity, these results suggest that in Caucasian subjects, simvastatin but not pravastatin could be a weak inducer of cytochrome P-450 3A. This contrasting effect could be related to the major pharmacological differences existing between these two drugs.

A pharmacokinetic evaluation of the second-generation H1-receptor antagonist cetirizine in very young children.

The pharmacokinetics of the second-generation H1-receptor antagonist cetirizine was studied in eight children younger than 4 years of age who were treated with a single dose of cetirizine solution (5 mg). These children were hospitalized with suspected allergic respiratory problems or recurrent respiratory tract infections. Blood samples were collected at 1/2, 1, 1 1/2, 2, 4, 6, 8, 12, and 24 hours, and a 24-hour urine collection was performed in five of the samples. The findings obtained in children were compared with those obtained in 16 healthy young adults (mean +/- SD, 24.6 +/- 4.1 years) who received a single 20 mg dose. Cetirizine was absorbed more slowly in children (p = 0.006; mean +/- SD, 1.44 +/- 1.12 hours) than in adults (0.62 +/- 0.22 hours). The plasma elimination half-life of cetirizine was significantly shorter in children (p < 0.001; 4.91 +/- 0.6 hours) than in adults (8.6 +/- 2.1 hours), and the clearance rate was significantly higher in children (p < 0.001; 1.48 +/- 0.41 ml/min/kg) than in adults (0.80 +/- 0.17 ml/min/kg). Urinary excretion of unchanged cetirizine was significantly lower in children (p < 0.001; 37.8% +/- 5.2%; n = 5) than in adults (57.7% +/- 11.8%). Therefore the metabolism of cetirizine is faster in young children than in adults. This effect must be taken into account in future pharmacodynamic studies in this age group.

Scoparone O-demethylase assay is not useful to differentiate the effects of model inducers of cytochrome P-450 in rabbit and guinea pig liver.

Coumarin derivative, scoparone (6,7-dimethoxycoumarin), is regioselectively O-demethylated into isoscopoletin (I) and scopoletin (S). This oxidation is inversely influenced by cytochrome P-450 inducers in the rat such as 3-methylcholantrene (3-MC) and phenobarbital (PB). The I/S ratio is higher than 1.5 with 3-MC treatment whereas it is lower than 0.5 with PB treatment. With regards to this contrasting effect, it has been suggested that the I/S ratio should be useful to differentiate between the effects of these types of inducers. We studied the consequences of in vivo PB and 3-MC treatment on scoparone biotransformation in guinea pig and rabbit. In these two species, at the basal state, scoparone biotransformation was enhanced in comparison to the rat. Moreover, in these untreated animals, two other metabolites were formed. After 3-MC or PB treatment, scoparone metabolism is, in contrast to the rat, inappropriate to differentiate between the P-450 profile of other animals.

Absence of CYP3A genetic polymorphism assessed by urinary excretion of 6 beta-hydroxycortisol in 102 healthy subjects on rifampicin.

A previous study has demonstrated that the urinary level of 6 beta-hydroxycortisol is a marker of liver CYP3A content after induction by rifampicin. To put in evidence an eventual genetic polymorphism for this cytochrome, the frequency distribution of 6 beta-hydroxycortisol excretion was investigated in 102 healthy Caucasians before and after 6 days of oral rifampicin administration (600 mg daily). After rifampicin treatment, a wide interindividual distribution was observed but no clear bimodality. Moreover the mean 6 beta-hydroxycortisol level was higher in women (n = 38) than in men (n = 64). These observations do not favour the existence of a CYP3A genetic polymorphism based on 6 beta-hydroxycortisol excretion but evoke a sexual dimorphism. However, CYP3A is composed of at least four enzymes and as the enzyme(s) responsible for cortisol 6 beta-hydroxylation is (are) not perfectly known, it can not be excluded that a genetic polymorphism does exist for one enzyme of this family.

Immunoquantification of cytochrome P-450 3A on rat paraffin-embedded liver tissue.

The cytochrome P-450 3A family is involved in the metabolism of several drugs, including nifedipine, cyclosporine, quinidine and erythromycin. The purpose of this study was to develop a reliable method to obtain a relative quantification of cytochrome P-450 3A apoproteins in rat liver specimens by immunocytochemistry and to correlate such quantification to erythromycin N-demethylase activity, a biochemical pathway sustained by that enzymatic system. Thirty-six male Wistar rats were treated with an injection of either saline or dexamethasone phosphate (10, 30 or 50 mg/kg), a potent inducer of cytochrome P-450 3A. Specimens taken from the same lobe were processed for immunocytochemistry and determination of erythromycin N-demethylase activity. Paraffin sections were treated with a polyclonal antiserum directed against cytochrome P-450 3A. The density of cytochrome P-450 3A immunostaining measured by an automatic image analyzer increased with the dose of dexamethasone pretreatment, and with the erythromycin N-demethylase activity, both parameters being closely correlated. Our data indicate that in rats, when cytochrome P-450 3A is concerned, there is a close correlation between the results of immunoquantitation and biochemical activity. This suggests that such a method of investigation might be used on small paraffin-embedded liver specimens obtained by needle biopsy.

Comparison of the effect of celiprolol and nifedipine on blood pressure and plasma lipids.

During a double-blind, randomized study in hypertensive patients, changes in blood pressure (BP) and in plasma lipid and lipoprotein levels during treatment with celiprolol were compared with those occurring during nifedipine treatment. Fifty-three patients (28 men and 25 women) with mild-to-moderate hypertension, aged 20-64 years, were studied. After a 1-month placebo run-in period, patients were randomly assigned to receive either nifedipine (40 mg daily) or celiprolol (200 mg daily) each time using a double dummy technique. After 6 weeks, dosages of each drug could be doubled. Both drugs caused similar reductions in blood pressure but after 12 weeks treatment, the percentage of decrease in diastolic BP (DBP) was more pronounced (p less than 0.01) in the nifedipine group (-18%) than in the celiprolol group (-12%). After 6 weeks, there were no differences in plasma lipids between the two treatment groups. However, the changes after 12 weeks treatment were different (p less than 0.05) between the groups, leading to lower levels of plasma esterified cholesterol, low-density lipoprotein (LDL) cholesterol and apoprotein AI, AII, and B in the celiprolol group. Plasma lecithin cholesterol acyltransferase activity (LCAT) was not modified, suggesting that reverse cholesterol transport was not affected by the drugs. In both treatment groups, a significant positive relationship was observed between changes in LDL cholesterol and apoprotein B. As compared with nifedipine, celiprolol after 12-week therapy had a rather favorable plasma lipid profile. The clinical relevance of such findings, in terms of prevention of cardiovascular complications, has yet to be established.

Effects of combined bezafibrate-simvastatin appraised in healthy subjects.

The occurrence of clinical and biochemical side effects of bezafibrate (400 mg daily) or simvastatin (20 mg daily) alone or combined was appraised in 13 healthy male normolipidemic subjects according to a single blind design. Each period of 2 weeks of treatment with bezafibrate or simvastatin or bezafibrate plus simvastatin was followed by a period of placebo (1 week). No subjects experienced myalgia or muscle weakness. Plasma creatine kinase (CK) elevations, particularly skeletal muscle CK (CK-MM), were observed in 6 subjects: 11 times during different placebo periods, 5 times on bezafibrate, 4 times on simvastatin, and 4 times on combined bezafibrate-simvastatin, but never reached 1,600 IU/L. Only a trend to an increase of CK mean values on combined bezafibrate-simvastatin was shown. The hepatic transaminase and gamma-glutamyltransferase activities remained unmodified throughout the trial, unlike alkaline phosphatase activity, which fell on bezafibrate and on bezafibrate plus simvastatin. The low-density lipoprotein cholesterol level was more reduced with simvastatin than with bezafibrate. The addition of bezafibrate to simvastatin did not decrease it further. Lecithin:cholesterol acyltransferase activity expressed as fractional esterification rate was enhanced only on simvastatin and bezafibrate-simvastatin.