The pharmacokinetics of caffeine in Nigerian children suffering from malaria and kwashiorkor

Objectives: Caffeine-containing beverages are generally consumed by Nigerians suffering from malaria and kwashiorkor in the belief that caffeine aids early recovery from these illnesses, which are common in the tropics. However, there are no studies on the influence of these diseases on the absorption and pharmacokinetics of caffeine in Africans. Materials and methods: A single oral dose of caffeine was given to five healthy children and to five and seven children suffering from malaria and kwashiorkor, respectively. Caffeine and its dimethylxanthine metabolites were measured in plasma using high-performance liquid chromatography. Results: The maximum plasma concentration (C_max) of caffeine and the time of C_max were similar (P > 0.05) in the three groups. However, the elimination half-life of caffeine was significantly longer in children with malaria (9.2 ± 3.5 h) (P < 0.01) and kwashiorkor (13.1 ± 7.9 h) (P < 0.05) than in the healthy controls (3.7 ± 1.8 h). The total plasma oral clearance of caffeine of 4.4 ± 1.9 ml/min/kg in healthy children was significantly higher (P < 0.01) than in those with kwashiorkor (2.0 ± 0.9 ml/min/kg) and malaria (1.6 ± 1.0 ml/min/kg) (P < 0.05). Paraxanthine was the principal metabolite in all the three groups with C_max significantly higher in healthy children (1.3 ± 0.3 μg/ml) than in children with malaria (0.8 ± 0.4 μg/ml) (P < 0.05) and kwashiorkor (0.3 ± 0.1 μg/ml) (P < 0.0001). CYP1A2 activity, measured by the plasma ratios of paraxanthine: caffeine, was significantly lower in kwashiorkor and malaria. Conclusions: This study showed that the plasma kinetics of caffeine are significantly altered in malaria and kwashiorkor, and CYP1A2 activity was lower in these two disease groups. Received: 12 April 1999 / Accepted in revised form: 30 November 1999     

Consistency and efficacy of cetirizine (10 mg) versus ebastine (20 mg) at 4 h on skin reactivity

Objective: We compared the consistency and efficacy of the two antihistamines, cetirizine (10 mg) and ebastine (20 mg) on histamine skin reactivity 4 h after treatment. Methods: Twenty-four healthy volunteers participated in a randomised double-blind cross-over study. The areas of wheals and flares induced by increasing (0, 5, 10, 50, 100, 200, 300 mg/ml) histamine concentrations, administered by prick tests, were measured before and 4 h after intake of cetirizine or ebastine. Results: Before treatment, concentration–response curves were similar and threshold concentrations identical (0.57 mg/ml and 0.57 mg/ml for cetirizine and ebastine, respectively). Both treatments exerted a significant effect. However, cetirizine was significantly more efficient than ebastine 20 mg (P < 0.01 both for wheals and flares). After cetirizine, the threshold concentration inducing a 3-mm² wheal was significantly higher (266 mg/ml) than after ebastine (77 mg/ml) (P < 0.01), and total inhibition of the wheal was obtained in 18 of 24 patients for cetirizine and in 4 of 24 for ebastine (P < 0.001). The variation coefficient for the wheal reaction was 31% for cetirizine and 159% for ebastine, indicating a much lower variability after cetirizine. Conclusion: Our study shows clearly that the efficacy of a single therapeutic dosage of cetirizine is greater and consistently better than that of ebastine for suppression of cutaneous reactivity to histamine 4 h after treatment in healthy volunteers. The need for ebastine to metabolise into the active carebastine might explain this difference. Received: 14 June 1999 / Accepted in revised form: 31 July 1999     

Contribution of age,body weight,and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients

Objective The objective of this study was to assess the contribution of the VKORC1 and CYP2C9 genotypes and age, body size, and weight of the patients to the warfarin dose requirement in a Chinese population. Methods Blood samples were collected from 178 Chinese patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5–3.0). The polymorphisms for the VKORC1 (-1639GA) and CYP2C9*3 genotypes, venous INR, and plasma concentration and unbound concentration of warfarin were then analyzed. Results VKORC1 (-1639G>A) genotyping showed that 149 patients were homozygous AA, 28 were heterozygous GA, and one was homozygous for the GG genotype. CYP2C9*3 genotyping showed that 162 patients were *1/*1, and 16 patients were heterozygous *1/*3. Patients with the VKORC1(-1639 GG+GA) (3.32 ± 1.02 mg/day) and CYP2C9*1/*1 (2.06 ± 0.82 mg/day) genotypes required a significantly higher warfarin dose than those with the -1639 AA (1.76 ± 0.57 mg/day; P < 0.001) or CYP2C9*1/*3 (1.60 ± 1.29 mg/day; P < 0.001), genotype. The multiple linear regression model for warfarin dose indicated significant contributions from age (r ² = 0.084; P < 0.001), weight (r ² = 0.063; P < 0.001), VKORC1 genotype (r ² = 0.494; P < 0.001), and age, weight, and CYP2C9 and VKORC1 genotype together (r ² = 0.628; P < 0.001). Conclusion This study shows that age, weight and the VKORC1 and CYP2C9 polymorphism affect warfarin dose requirements in our sample of Chinese patients receiving long-term therapy and showing stable control of anticoagulation. It is anticipated that the use of dosing regimens modified by taking into account the contribution of age, weight, and the CYP2C9 and VKORC1 genotypes has the potential to improve the safety of warfarin therapy.     

Effect of itraconazole on cerivastatin pharmacokinetics

Objective: To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods: A randomized, double-blind, cross-over study design with two phases, which were separated by a wash-out period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h. Results: Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC_0–∞) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (C_max) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC_0–24 h 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t_1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC_0–24 h of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC_0–24 h of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC_0–24 h and t_1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole. Conclusions: Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors. Received: 28 June 1998 / Accepted in revised form: 10 October 1998     

Therapeutic amoxicillin levels achieved with oral administration in term neonates

Aims The standard treatment of neonatal group B Streptococcus infection is intravenous amoxicillin for 10 days. We investigated whether effective serum amoxicillin concentrations could be reached by switching to oral amoxicillin after 48 h of intravenous administration in full-term neonates with group B Streptococcus infection. Methods Over 2 years, we included 222 full-term neonates who had early onset group B streptococcal disease responsive to 48 h of intravenous amoxicillin, at which point they were asymptomatic and fed orally. They were switched to oral amoxicillin (300 or 200 mg/kg per day in four divided doses). Steady-state serum amoxicillin concentrations were determined 48 h later by high-performance liquid chromatography; values ≥5 mg/l were considered effective. Results Mean gestational age was 39.32 ± 1.5 weeks ,and mean birth weight was 3,422 ± 533 g; 29 newborns were bacteremic. Median serum amoxicillin concentration on oral therapy was 31,.15 (range 11–118) and 25.80 (range 5–84.8) with 300 and 200 mg/kg per day, respectively. None of the infants had a concentration <5 mg/l (p < 0.001). Gastrointestinal tolerance was satisfactory; 216 patients were discharged at 5 days of age, and none was readmitted within the 3-month follow-up. Conclusion Early switching to the oral route in asymptomatic full-term newborns with early onset group B streptococcal disease maintained serum amoxicillin concentrations within our predefined therapeutic range (error risk<0.001). This strategy may hold potential for reducing treatment invasiveness and shortening hospital length of stay.     

The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans

Objective: The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers. Methods: The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8–14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity. Results: Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (±SD) of R-6-hydroxywarfarin (31.1 ± 7.4 ml/h baseline; 18.5 ± 4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9 ± 1.3 ml/h baseline; 4.3 ± 1.1 ml/h at end of cimetidine treatment; P < 0.01). Conclusion: Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients. Received: 11 December 1998 / Accepted in revised form: 17 March 1999     

Changes in urinary PGE<Subscript>2</Subscript> after ibuprofen treatment in preterm infants with patent ductus arteriosus

Purpose  To investigate changes in urinary PGE₂ after ibuprofen treatment in preterm infants with patent ductus arteriosus (PDA). Methods  Twenty preterm infants with a hemodynamically significant PDA (gestational age, 28.6 ± 2.3 weeks) and 20 controls (gestational age, 30.4 ± 1.5 weeks) were prospectively enrolled at 48–72 h of life. After enrollment, the former underwent conventional ibuprofen-lysine treatment. At 48–72 h (T₀) and 108–144 h of life (T₁), urine samples were noninvasively collected in both groups to measure urinary PGE₂ concentrations (enzyme immunoassay method), and renal function was investigated. Results  Urinary PGE₂ decreased significantly both in ibuprofen-treated patients (66.95 ± 16.78 vs. 27.15 ± 17.92 pg/mL, P < 0.001) and in controls (71.7 ± 16.2 vs. 53.2 ± 18.4 pg/mL, P < 0.001) from T₀ to T₁. However, urinary PGE₂ at T₁ was significantly lower (P < 0.001) in the ibuprofen group compared to the control group. Acute renal failure occurred in three ibuprofen-treated patients (15%). Conclusions  Ibuprofen markedly reduces (59.4%) urinary PGE₂ and may alter renal function in the newborn.     

Lower Glial Metabolite Levels in Brains of Young Children with Prenatal Nicotine Exposure

Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3–4 years old) children, using proton magnetic resonance spectroscopy (¹H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/¹H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA—p = 0.03) and tCr levels (repeated measures ANOVA–p = 0.003), especially in the basal ganglia of the girls (−19.3%, p = 0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p = 0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r = −0.67; p < 0.001) and visual motor integration (r = −0.53; p = 0.01). The amount of prenatal nicotine exposure did not correlate with metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls.     

Grapefruit juice can increase the plasma concentrations of oral methylprednisolone

Objective: To investigate whether the pharmacokinetics of orally administered methylprednisolone and plasma cortisol concentrations are affected by administration of grapefruit juice. Methods: In a randomised, two-phase, cross-over study, ten healthy subjects received either 200 ml double-strength grapefruit juice or water three times a day for 2 days. On day 3, 16 mg methylprednisolone was given orally with 200 ml grapefruit juice or water. Additionally, 200 ml grapefruit juice or water was ingested 0.5 h and 1.5 h after methylprednisolone administration. Plasma concentrations of methylprednisolone and cortisol were determined using liquid chromatography/mass spectrometry (LC/MS/MS) over a 47-h period. Results: Grapefruit juice increased the total area under the plasma methylprednisolone concentration–time curve (AUC_0–∞) by 75% (P < 0.001) and the elimination half-life (t _1/2) of methylprednisolone by 35% (P < 0.001). The peak plasma concentration of methylprednisolone (C_max) was increased by 27% (P < 0.01). Grapefruit juice delayed the time to the C_max from 2.0 h to 3.0 h (P < 0.05). There was no significant difference in the plasma cortisol concentrations, measured after methylprednisolone administration, between the water and grapefruit juice phases. However, grapefruit juice slightly decreased the morning plasma cortisol concentrations before methylprednisolone administration (P < 0.05). Conclusions: Grapefruit juice given in high amounts moderately increases the AUC_0–∞ and t _1/2 of oral methylprednisolone. The increase in t _1/2 suggests that grapefruit juice can affect the systemic methylprednisolone metabolism. The clinical significance of the grapefruit juice–methylprednisolone interaction is small, but in some sensitive subjects high doses of grapefruit juice might enhance the effects of oral methylprednisolone. Received: 17 February 2000 / Accepted in revised form: 9 May 2000     

Effects of α-tocopherol on nerve conduction velocity and regeneration following a freeze lesion in immature diabetic rats

We investigated whether anti-oxidant treatment with α-tocopherol (1 g kg^–1 day^–1) could prevent the blunting of the normal maturational increase in motor and sensory nerve conduction velocity when diabetes is induced by streptozotocin in young rats. A further study in the same rats examined effects on myelinated fibre regeneration distance 14 days after a punctate sciatic nerve lesion by a liquid nitrogen cooled probe. In non-diabetic rats between 8 and 14 weeks of age, sciatic motor and saphenous sensory conduction velocity increased by approximately 28% (P < 0.001) and 21% (P < 0.001) respectively. Diabetes induced at 8 weeks blunted this maturational change by 65% for sciatic motor and almost completely for saphenous sensory fibres (P < 0.001). Treatment with α-tocopherol from diabetes induction totally prevented motor conduction velocity deficits (P < 0.001). For sensory saphenous nerve, conduction abnormalities were markedly attenuated (72%, P < 0.001) although a significant deficit remained compared to age-matched non-diabetic rats (P < 0.01). Sciatic nerve myelinated fibre regeneration distance, 14 days post lesion, was 15% reduced (P < 0.001) by untreated diabetes. However, in diabetic rats treated with α-tocopherol, regeneration distance was significantly improved (P < 0.001), being within the non-diabetic range. Thus, the data highlight the importance of reactive oxygen species in the aetiology of impaired nerve maturation and regeneration in experimental diabetes and indirectly support the view that anti-oxidant treatment could have a therapeutic role in patients. Received: 23 July 1996 / Accepted: 26 September 1996     

The effects of acute falciparum malaria on the disposition of caffeine and the comparison of saliva and plasma-derived pharmacokinetic parameters in adult Nigerians

Objectives: The pharmacokinetics of caffeine and its dimethylxanthine metabolites were evaluated in Nigerians, for whom it is normal to consume caffeine-containing beverages during ill health and recuperation in the belief that caffeine aids early recovery from illness; however, there are no data defining the kinetics of caffeine in healthy and ill Nigerians. Materials and methods: A single oral dose of 300 mg caffeine was given to ten healthy adult Nigerians and ten adults suffering from acute uncomplicated Plasmodium falciparum malaria infection. Caffeine and its dimethylxanthine metabolites were measured in plasma and saliva of healthy subjects and in plasma of patients suffering from malaria using high-performance liquid chromatography. Results: The plasma pharmacokinetics of caffeine per se in both groups was similar (P > 0.05). The maximum plasma concentration (C_max) of paraxanthine was significantly lower (P < 0.05) in malaria (0.9 ± 0.4 μg/ml) than in healthy controls (1.4 ± 0.5 μg/m1), and the paraxanthine:caffeine area under the plasma concentration–time curve ratio, an index of cytochrome P₄₅₀ (CYP)IA2 activity was significantly lower (P < 0.05) in malaria patients (0.5 ± 0.1) than in healthy controls (0.3 ± 0.2). The elimination half-life of theophylline was longer in malaria, while the area under the plasma concentration–time curve of theobromine was significantly higher (P < 0.05) in malaria (7.1 ± 3.4 μg ml⁻¹ h) than in healthy adults (4.1 ± 2.2 μg ml⁻¹ h). Excellent correlations were found between saliva and plasma concentrations of caffeine (r ²=0.98) with a mean saliva:plasma concentrations ratio of 0.7 ± 0.1. The plasma concentrations (C_max and AUC) were therefore higher than the corresponding salivary levels, so that the apparent oral clearance calculated for saliva exceeded the true oral clearance based on plasma data. Conclusions: Acute Plasmodium falciparum malaria produced significant changes in the disposition of caffeine metabolites. Analysis of concentrations in saliva is a useful non-invasive method for monitoring the kinetics of caffeine and paraxanthine in Nigerians. Received: 14 April 1999 / Accepted in revised form: 30 November 1999     

Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI)

Objective To investigate the influence of paroxetine on metoprolol concentrations and its effect in patients treated for acute myocardial infarction (AMI) who are routinely given paroxetine as a co-treatment of depression. Methods We recruited 17 depressed AMI patients who received metoprolol as a routine part of their therapy (mean dose 75 ± 39 mg/day). Patients were genotyped for CYP2D6 *3, *4 and gene duplication. Metoprolol and α-hydroxy-metoprolol were analyzed in plasma 0, 2, 6 and 12 h post-dose. Heart rates (HR) at rest were registered after each sampling. Paroxetine 20 mg daily was then administered, and all measurements were repeated on day 8. Results All patients were genotypically extensive metabolizers (EMs) (nine with *1/*1 and eight with *1/*3 or *4). Following the administration of paroxetine, mean metoprolol areas under the concentration–time curve (AUC) increased (1064 ± 1213 to 4476 ± 2821 nM × h/mg per kg, P = 0.0001), while metabolite AUCs decreased (1492 ± 872 to 348 ± 279 n M × h/mg per kg, P < 0.0001), with an increase of metabolic ratios (MR) (0.9 ± 1.3 to 26 ± 29; P < 0.0001). Mean HRs were significantly lower after the study week at each time point. Mean area under the HR versus time curve (AUEC) decreased (835 ± 88 to 728 ± 84 beats × h/min; P = 0.0007). Metoprolol AUCs correlated with patients’ AUECs at the baseline (Spearman r  = −0.64, P < 0.01), but not on the eighth day of the study. A reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. No other adverse effects of the drugs were identified. Conclusion A pronounced inhibition of metoprolol metabolism by paroxetine was observed in AMI patients, but without serious adverse effects. We suggest, however, that the metoprolol dose is controlled upon initiation and withdrawal of paroxetine.     

Estimation of CYP2C19 activity by the omeprazole hydroxylation index at a single point in time after intravenous and oral administration

Objective The purpose of this study was to identify the common time point to achieve hydroxylation index (HI: omeprazole plasma concentration/5-hydroxyomeprazole plasma concentration) reflecting AUC_OPZ/AUC_5OH-OPZ after intravenous (IV) and oral (PO) administration. Methods Twenty young and 28 elderly healthy subjects, including different CYP2C19 genotypes, were enrolled in the study. The young subjects received either 40 mg PO or 20 mg IV omeprazole, whereas the elderly subjects received 10 mg IV. The relation between AUC_OPZ/AUC_5OH-OPZ and HI was determined by Spearman’s rank correlation. Multiple stepwise linear regression analysis was performed to identify the common time point to calculate HI that reflects AUC_OPZ/AUC_5OH-OPZ after IV. Results In the correlation between HI and AUC_OPZ/AUC_5OH-OPZ IV at observed time points, HI_3h showed the highest correlation coefficients (r = 0.894, p < 0.001) in all 48 subjects. The correlation of HI between IV and PO at observed time points showed that HI_3h was highest (r = 0.916, p < 0.001) in 20 young subjects. Additionally, there was no significant difference between HI_3h of IV and that of PO (12.9 ± 15.9 and 12.9 ± 15.1, p = 0.997). The regression equation of HI_3h was the best to estimate AUC_OPZ/AUC_5OH-OPZ (AUC_OPZ/AUC_5OH-OPZ = 1.37 • HI_3h + 0.18 • Age – 7.83, r ² = 0.883, p < 0.001). Conclusions This study demonstrated that HI_3h after omeprazole IV was able to estimate AUC_OPZ/AUC_5OH-OPZ, as well as HI_3h after PO. Additionally, CYP2C19 activity can be estimated more definitely by using HI after omeprazole IV without intestinal absorption.     

A double-blind study of MPV-2213ad, a novel aromatase inhibitor, in healthy male subjects

Objective: Novel aromatase inhibitors are developed with requirements of high potency and selectivity for the aromatase enzyme. The hormonal effects of a new, non-steroidal competitive inhibitor of the aromatase enzyme, MPV-2213ad, were investigated in this study. Methods: The study was conducted as a double-blind, placebo controlled phase I study, where 32 healthy male volunteers were randomized to receive a single oral dose of either 0.3, 3 or 100 mg of MPV-2213ad or placebo. Serum concentrations of estradiol (E2), testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), cortisol and aldosterone were determined from samples taken 0, 4, 8 h and 12 h during the day of drug administration and 1, 2, 4 and 7 days after drug intake. The individual diurnal variation of circulating hormone concentrations was determined in all participants at 0, 4, 8 h and 12 h on the day before drug intake. Specimens for hematological and biochemical analyses were also collected. Results: A dose-dependent and statistically significant (P < 0.001) decrease in serum E2 concentrations was induced by MPV-2213ad. Lowest mean values were observed 8–12 h after drug administration and at 24 h the reductions were 10%, 34% and 69% from baseline in the 0.3-mg, 3-mg and 100-mg groups, compared with an 18% increase in the placebo group. Serum E2 concentrations returned to baseline within 4 days in all study subjects. A significant increase was observed in the serum concentrations of testosterone (P = 0.016), LH (P = 0.002) and FSH (P < 0.001) after administration of MPV-2213ad. Serum concentrations of cortisol and aldosterone were unaffected by MPV-2213ad. The drug was well tolerated. Conclusion: Single oral doses of MPV-2213ad, given to healthy male subjects, induced hormonal effects typical for a specific and selective inhibitor of the aromatase enzyme. Importantly, this study design with the determination of the diurnal rhythm in the levels of the corresponding hormones gives additional validity on the results. Received: 2 June 1998 / Accepted in revised form: 3 October 1998     

Efficacy of activated charcoal versus gastric lavage half an hour after ingestion of moclobemide, temazepam, and verapamil

Objective: To compare the efficacy of activated charcoal and gastric lavage in preventing the absorption of moclobemide, temazepam, and verapamil 30 min after drug ingestion. Methods: In this randomized cross-over study with three phases, nine healthy volunteers received a single oral dose of 150 mg moclobemide, 10 mg temazepam, and 80 mg verapamil after an overnight fast. Thirty minutes later, they were assigned to one of the following treatments: 25 g activated charcoal as a suspension in 200 ml water, gastric lavage (10 × 200 ml), or 200 ml water (control). Plasma concentrations of moclobemide, temazepam, and verapamil were determined up to 24 h. Results: Activated charcoal reduced the area under the plasma concentration–time curve from 0 h to 24 h (AUC_0–24 h) of moclobemide and temazepam by 55% (P < 0.05) and by 45% (P < 0.05), respectively. The AUC_0–24 h of verapamil was not significantly reduced by charcoal. Gastric lavage decreased the AUC_0–24 h of moclobemide by 44% (P < 0.05), but had no significant effect on that of temazepam or verapamil. The peak plasma concentration (C_max) of moclobemide, temazepam, and verapamil was reduced by 40%, 29% (P < 0.05), and 16%, respectively, by activated charcoal. Gastric lavage did not significantly decrease the C_max of any of these drugs. Conclusion: The absorption of moclobemide, temazepam, and verapamil can be moderately reduced by activated charcoal given 30 min after drug ingestion, while gastric lavage seems to be less effective. Received: 15 December 1999 / Accepted in revised form: 16 March 2000     

Chlorzoxazone: a probe drug whose metabolism can be used to monitor toluene exposure in rats

In this study we investigated cytochrome P450 (CYP) 2E1 expression using a probe drug, chlorzoxazone (CZX), whose metabolism can be used to monitor toluene exposure in rats. The animals received an i.p. injection of toluene (0.25, 0.5 and 1 ml/kg) once a day for 3 days. The total CYP and CYP2E1 content and the aniline and CZX hydroxylase activity (V _max and CL_int) increased depending on the dose of toluene administered. At the highest concentration (128 mM) of diethyldithiocarbamate, a specific inhibitor of CYP2E1, the production of 6-hydroxychlorzoxazone (HCZX) in microsomes from toluene-treated rats was reduced by about 80%. The IC₅₀ values in microsomes from toluene-treated rats were between 3 and 5 μM. The production of HCZX and the activity of aniline hydroxylase in toluene-treated rats were correlated with the amount of rat CYP2E1 protein (r=0.88 and r=0.88, respectively). The elimination of CZX by toluene-treated rats was increased and the HCXZ production in the toluene-treated group was greater than that in the olive oil control group. The correlations between intrinsic clearance (CL_int: V _max/K _m) in vitro and total body clearance (CL_tot) of CZX hydroxylation and the elimination half-life (t _1/2) of CZX in vivo in toluene-treated rats were high (r=0.784, P < 0.001; r=−0.678, P < 0.001, respectively). In addition, the metabolic plasma HCZX/CZX ratio did not require multiple blood sampling and 2 h after CZX administration in vivo there was also a high correlation with CL_int (V _max/K _m) in vitro (r=−0.729, P < 0.001). In conclusion, these results demonstrate that CZX is a very good probe for monitoring induction in toluene-treated rats. Received: 28 September 1999 / Accepted: 10 January 2000     

Performance of gentamicin population kinetic parameters in Portuguese neonates

Aim To evaluate the performance of eight different sets of gentamicin populational pharmacokinetic parameters, regarding potential implementation in clinical pharmacokinetic software as prior information. Methods The study involved 49 patients of 31.3±4.1 weeks of gestational age (GA), receiving gentamicin, and for whom peak and trough concentrations were obtained. Accuracy and precision were assessed by mean prediction error (ME), mean squared prediction error (MSE) and root mean squared prediction error (RMSE). Weighted prediction-error analysis was carried out in order to evaluate peak and trough concentrations together (ME_w, MSE_w and RMSE_w). Results The analysis showed CL=0.036 l/h/kg (<34 weeks GA) or CL=0.051 l/h/kg (≥34 weeks GA), and V _d =0.5 l/kg (≤37 weeks GA) or V _d =0.4 l/kg (>37 weeks of GA) as the most accurate and precise set of pharmacokinetic parameters (Set 4), presenting the highest percentage of clinically acceptable estimates (Error_Peak<1 μg/ml, and Error_Trough <0.375 μg/ml). Conclusion The adoption of the previously mentioned set of parameters as population estimates seems to be the best option, bearing in mind the obtained results. However, we strongly believe that pharmacokinetic parameter determination of gentamicin should be carried out whenever possible in order to improve the rationale and cost-effectiveness of therapy.     

Serum and urinary boron levels in rats after single administration of sodium tetraborate

The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6 ± 7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t _1/2a=0.608±0.432 h; elimination half-life, t _1/2=4.64±1.19 h; volume of distribution, Vd=142.0±30.2 ml/100 g body wt.; total clearance, C _tot=0.359 ± 0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (C _max) was 2.13 ± 0.270 mg/l, and the time needed to reach this maximum concentration (T _max) was 1.76 ± 0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication. Received: 1 December 1997 / Accepted: 24 March 1998     

Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the early period of treatment

Objective: The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months) after the start of antipsoriatic therapy. Methods: Ten male and female psoriatic patients who failed to respond to previous conventional therapy were treated with 15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the same occasions, MTX accumulation in erythrocytes obtained before MTX administration was investigated. Pharmacodynamics of MTX were evaluated using the psoriasis area and severity index (PASI) score. Results: There were marked intersubject differences (range of coefficients of variation 34.9–76.3%) in the area under the curve (AUC), peak concentration (C_max) and clearance (CL) of MTX. Total CL was proportional to renal clearance (CL_R) (r ² = 0.735, P < 0.0001) which accounted for 73 (19)% of the former. There was a strong linear relationship (r ² = 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of drug administration, the urinary excretion of MTX was 46–99% of the dose, while that of 7-OH MTX was 1.5–8.6%. In 8 of 10 patients, more than 70% of the MTX dose was recovered. No intraindividual variations of MTX kinetic parameters during treatment were observed. MTX concentrations in erythrocytes reached the steady-state concentration in the range 40.7–170 nmol · l⁻¹ after 2 months of therapy. Pharmacodynamic measurement versus pharmacokinetics revealed a significant inverse relationship between PASI score and MTX AUC (r _s = −0.912, P < 0.002) and between PASI score and erythrocytic MTX (r _s = −0.988, P < 0.002). Conclusion: The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration. Received: 15 April 1997 / Accepted in revised form: 18 July 1997     

Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart

Objective: With the aim to obtain a premixed rapid-acting insulin with a serum insulin profile more closely resembling the endogenous meal-stimulated serum insulin profiles, a 30/70 (rapid/intermediate-acting) premixed suspension of the rapid-acting insulin analogue insulin aspart (BIAsp30) was compared with a similar premixed suspension of biphasic human insulin 30/70 (BHI30) after a single subcutaneous injection. Methods: The study had a randomised, double-blind, two-period crossover design. Twenty-four healthy male subjects received a single subcutaneous dose of either 0.2 U · kg⁻¹ bodyweight of BIAsp30 or BHI30 on two study days. Results: BIAsp30 was absorbed faster than BHI30, as reflected in the area under the insulin concentration-time curve from 0 to 90 min after dosing [AUC_{(0–90 min)}]. This was significantly larger for BIAsp30 than for BHI30 (1403 ± 372 versus 752 ± 191 mU · l⁻¹ · min⁻¹ [mean ± SD]; P < 0.0001). Furthermore, the time to maximum serum insulin concentration (t_max) of BIAsp30 was approximately half the t_max of BHI30 (60 [45–70] versus 110 [90–180] min [median, interquartile range]; P=0.0001) and the maximum insulin concentration (C_max) was significantly higher for BIAsp30 than for BHI30 (23.4 ± 5.3 versus 15.5 ± 3.7 mU · l⁻¹ [mean ± SD]; P < 0.0001). The serum glucose profiles showed a significantly earlier onset of the glucose-lowering effect following BIAsp30 than following BHI30. Conclusions: The improved absorption properties of soluble insulin aspart in its premixed formulation provide a basis for a more efficient meal-related glucose control and immediate pre-meal delivery when compared with a similar human premixed insulin in the treatment of diabetes mellitus. Received: 22 November 1999 / Accepted in revised form: 7 April 2000