Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations

Objective The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes. Methods Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases. Results Mean omeprazole AUC (0,∞) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose. Conclusion This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.     

Lack of acetaminophen ceiling effect on R-III nociceptive flexion reflex

Objective: The analgesic efficacy of intravenous doses of acetaminophen (paracetamol) 0.5 g, 1 g and 2 g (administered as propacetamol) was assessed in 11 healthy subjects in a randomised, double-blind, placebo-controlled crossover study. The antinociceptive effect was assessed over 8 h by measurement of the nociceptive flexion reflex threshold (R-III) in response to selective transcutaneous electrical stimulations. Results: After acetaminophen 0.5 g, R-III increased to a mean maximum of 23% over baseline values; after 1 g to 28%, and after 2 g to 40%. The AUC_0–8 h of the analgesic effects and the AUC_0–8 h of plasma concentrations closely correlated and were dose-dependent: r _s = 0.37, for R-III and r _s = 0.94, for the plasma concentrations. Intravenous acetaminophen exerted a dose-dependent central antinociceptive effect. Received: 19 August 1996 / Accepted in revised form: 18 August 1997     

Omeprazole limited sampling strategies to predict area under the concentration–time curve ratios: implications for cytochrome P450 2C19 and 3A phenotyping

Purpose  

To develop a limited sampling strategy (LSS) to predict area under the concentration–time curve (AUC) ratios of omeprazole (AUC_OPZ) to its metabolites 5-hydroxyomeprazole (AUC_5OH) and omeprazole sulfone (AUC_SUL) as phenotyping parameters for cytochrome P450 (CYP) 2C19 and 3A.     

CYP2C19 genotypes and omeprazole metabolism after single and repeated dosing when combined with clarithromycin

Objectives: Omeprazole is metabolized mainly by CYP2C19 which has two major mutations (CYP2C19*2 in exon5 and CYP2C19*3 in exon4) associated with the poor metabolizer (PM) phenotype. The aim of this study was to examine the relationship between genetic polymorphism of CYP2C19 and metabolism of omeprazole administrated as a single dose or as repeated-doses, which were in both cases co-administered with clarithromycin. Methods: Twelve healthy Japanese subjects were typed for CYP2C19 polymorphism. In the single-dose study, plasma levels of omeprazole and its metabolites were measured for 24 h after administration of 20 mg omeprazole and 400 mg clarithromycin to six healthy Japanese subjects. In the repeated-dose study, plasma levels of omeprazole and its metabolites were measured after repeated oral administration of 20 mg omeprazole and 400 mg clarithromycin twice daily for 6 days and then after 20 mg omeprazole and 400 mg clarithromycin once on the 7th day to the other 6 healthy Japanese subjects. Results: In the single-dose study, the areas under the plasma concentration-versus-time curve (AUCs) of omeprazole of homozygotes for the wild-type allele (*1/*1 n = 2), heterozygotes (n = 3) for the CYP2C19*2 (*1/*2) or for the CYP2C19*3 (*1/*3) and heterozygote (n = 1) for the two defects (*2/*3) were on average 450, 1007 and 6710 ng · h⁻¹ · ml⁻¹, respectively. The ratios of AUCs of omeprazole/5-hydroxyomeprazole for *1/*1, *1/*2 or *1/*3 and *2/*3 were 1, 2 and 30, respectively. In the repeated-dose study, the AUCs of omeprazole for *1/*1, *1/*2 or *1/*3 and *2/*3 were 4041 (n = 2), 3149 (n = 3) and 6684 (n = 1) ng · h⁻¹ · ml⁻¹, respectively. The ratios of AUCs of omeprazole/5-hydroxyomeprazole for *1/*1, *1/*2 or *1/*3 and *2/*3 were 7, 11 and 30, respectively. In the repeated-dose study, the AUC of omeprazole of *1/*1 genotypes was nine-fold higher, that of *1/*2 and *1/*3 genotypes was three-fold higher, and the C_max value of omeprazole was three-fold higher compared with subjects with the same genotype in the single-dose study. However, there were few differences in the AUC and C_max of omeprazole between the *2/*3 genotype in the single-dose study and the homozygote for the CYP2C19*2 (*2/*2) in the repeated-dose study. Conclusion: Subjects with *1/*1, *1/*2 and *1/*3 genotypes in the repeated-dose study had lower CYP2C19 activity than subjects of the same genotype in the single-dose study. The difference in omeprazole metabolism between subjects with different genotypes observed on day 1 seemed to disappear after 7 days of repeated-dose administration. Received: 5 June 1998 / Accepted in revised form: 27 October 1998     

The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin

Objective Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing α- and β-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects. Methods This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose. Results Exposure to vildagliptin (AUC_0–∞ and C_max) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC_0–∞, 0.80 (0.60, 1.06), p = 0.192; C_max, 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [−8% for AUC_0–∞, geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; −23% for C_max, geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C_max was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC_0–∞ was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC_0–∞ and C_max were increased by 29–84% and 24–63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment. Conclusions There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.     

A PET study on regional coexpression of 5-HT<Subscript>1A</Subscript> receptors and 5-HTT in the human brain

Rationale Several lines of evidence suggest inter-dependency between the serotonin transporter (5-HTT) and the 5HT_1A receptor, two recognised targets for the treatment of anxiety and depression. Objectives to examine the correlation of regional expression levels for these two serotonergic markers in the human brain in vivo. Methods Twelve male control subjects were examined with PET twice on the same day, using the radioligands [¹¹C]WAY 100635 and [¹¹C]MADAM for quantification of the 5-HT_1A receptor and the 5-HTT, respectively. The binding potential (BP) was calculated for raphe nuclei, hippocampus and frontal cortex. Results In all regions, the BP for both [¹¹C]WAY 100635 (raphe nuclei 1.85–4.71, hippocampus 2.52–6.17, frontal cortex 2.03–3.79) and [¹¹C]MADAM (2.70–7.65, 0.47–1.76, 0.18–0.51) varied several fold between subjects. In the raphe nuclei, where the two markers are situated on the same neurons, the ratio of [¹¹C]WAY 100635 binding to [¹¹C]MADAM BP binding varied considerably (0.43–1.05). There was a positive correlation between the two markers in the raphe nuclei (r _xy = 0.68, p < 0.05) and in the hippocampus (r _xy = 0.97, p < 0.001) but not in the frontal cortex (r _xy = −0.25, p = 0.44). Conclusions The results support a correlation between density levels of the 5-HT_1A-receptor and the 5-HTT in the raphe nuclei and hippocampus but not in the frontal cortex. A suggested clinical implication is that the inter-individual variability in 5-HT_1A-receptor and 5-HTT densities, as well as the ratio of these, is of particular interest in relation to individual responses to selective serotonin reuptake inhibitor treatment.     

Comparative analysis of the experimental and clinical pharmacokinetics of Amiodarone

The pharmacokinetics of two tablet formulations of amiodarone – Amiodarone and Amiodaron-Akri – were studied in 12 rabbits and 18 healthy human volunteers after single p.o. doses of 200 mg. A highly statistically significant correlation was found between plasma amiodarone concentrations in rabbits and volunteers (r = 0.8263, p < 0.001). Normalized C _max and AUC _0−∞ values were significantly greater in volunteers than rabbits, while specific V _Z and Cl _t values were lower and MRT was significantly higher; rate coefficients of absorption and measures of relative bioavailability showed no statistically significant differences between rabbits and healthy humans.     

The bioavailability of bromazepam, omeprazole and paracetamol given by nasogastric feeding tube

Aims

To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers.

Methods

In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography–UV, pharmacokinetic parameters (C_max, ${\text{AUC}}_{0 - \infty } Aims  To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers. Methods  In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography–UV, pharmacokinetic parameters (C_max, , t_?, k_e, t_max) were compared statistically, and C_max, and t_max were analyzed for bioequivalence. Results  A statistically significant difference was seen in the of bromazepam, with nasogastric administration decreasing availability by about 25%: AUC_OR = 2501 ng mL⁻¹ h; AUC_NT = 1855 ng mL⁻¹ h (p < 0.05); ratio (geometric mean) = 0.74 [90% confidence interval (CI) 0.64–0.87]. However, this does not appear to be clinically relevant given the usual dosage range and the drug’s half-life (approx. 30 h). A large interindividual variability in omeprazole parameters prevented any statistical conclusion from being drawn in terms of both modes of administration despite their similar average profile: AUC_OR = 579 ng mL⁻¹ h; AUC_NT = 587 ng mL⁻¹ h (p > 0.05); ratio (geometric mean) = 1.01 (90% CI 0.64–1.61). An extended study with a larger number of subjects may possibly provide clearer answers. The narrow 90% confidence limits of paracetamol indicate bioequivalence: AUC_OR = 37 μg mL⁻¹ h; AUC_NT = 41 μg mL⁻¹ h(p > 0.05); ratio (geometric mean) = 1.12 (90% CI 0.98–1.28). Conclusion  The results of this study show that the nasogastric route of administration does not appear to cause marked, clinically unsuitable alterations in the bioavailability of the tested drugs.     

Comparison of several approaches of therapeutic drug monitoring of cyclosporin A based on individual pharmacokinetics

Objective: The clinical outcome of patients after organ transplantation is correlated with cyclosporin A (CyA) exposure. It is generally accepted that the area under the concentration–time curve (AUC) provides a reliable means for drug exposure. However, in routine therapeutic drug monitoring (TDM) of CyA, trough levels are mostly used. Currently, a number of different new concepts of CyA-TDM, including approaches such as single, double or triple time-point and abbreviated AUC determinations, have been introduced. The purpose of this study was to compare the predictive value of the different strategies of TDM. Methods: Calculations were based on 40 individual concentration–time profiles after oral administration of CyA to patients who had been included into an ongoing prospective clinical trial. Non-compartmental analysis was used to calculate the AUC_0–12h. Multiple linear regression was performed to describe the relationship between the different sets of blood concentrations and the respective AUC_0–12h as well as to evaluate their predictive value regarding AUC. Predictive performance was assessed by prediction bias and prediction precision, which were estimated as the mean prediction error and root mean squared error, respectively. Results: When comparing the various combinations of time points, it was found that one-point approaches showed the strongest differences with regard to the predictive value; the associated r² values differed from 0.203 to 0.792. The two and three time-point approaches showed lower differences – r² 0.802–0.972. The four-point and five-point approaches (r² 0.942–0.982) were the strongest predictors for CyA AUC_0–12h. Relative bias ranged from −27.7% to 63.8% and changed significantly when multiple-point predictors were used. In those cases, the predictive performance improved. Considering the predictive performance as well as the smallest bias and highest prediction precision, C3, C1 + C3, C1 + C3 + C6 and C1 + C2 + C3 + C6 were the best predictors. Conclusion: The results of this study indicate that in kidney transplant patients a clinically sufficient precise estimation of the CyA AUC is possible using two or three concentration–time points. Received: 18 November 1999 / Accepted in revised form: 10 February 2000     

The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

Purpose Sorafenib is a small molecule inhibitor of multiple signaling kinases thought to contribute to the pathogenesis of many tumors including brain tumors. Clinical trials with sorafenib in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model. Methods 7.3 mg/kg of sorafenib free base equivalent solubilized in 20% cyclodextrin was administered IV over 1 h to three adult rhesus monkeys. Serial paired plasma and CSF samples were collected over 24 h. Sorafenib was quantified with a validated HPLC/tandem mass spectrometry assay. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUC_CSF : AUC_plasma. Results Peak plasma concentrations after IV dosing ranged from 3.4 to 7.6 μg/mL. The mean ± standard deviation (SD) area under the plasma concentration from 0 to 24 h was 28 ± 4.3 μg•h/mL, which is comparable to the exposure observed in humans at recommended doses. The mean ± SD clearance was 1.7 ± 0.5 mL/min/kg. The peak CSF concentrations ranged from 0.00045 to 0.00058 μg/mL. The mean ± SD area under the CSF concentration from 0 to 24h was 0.0048 ± 0.0016 μg•h/mL. The mean CSF penetration of sorafenib was 0.02% and 3.4% after correcting for plasma protein binding. Conclusion Sorafenib is well tolerated in NHP and measurable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.     

Use of omeprazole sulfone in a single plasma sample as a probe for CYP3A4

Objective The hydroxylation of omeprazole, measured as the ratio of omeprazole/5-hydroxyomeprazole in a plasma sample taken 3 h after an oral dose, is an established method to determine CYP2C19 activity, and the ratio of omeprazole AUC/omeprazole sulfone AUC has been used for assessing CYP3A4 activity. The aim of this study was to determine whether the latter ratio from a single 3-h sample can also be used for CYP3A4 phenotyping.Methods Plasma levels of omeprazole and omeprazole sulfone were analyzed by reversed-phase high-performance liquid chromatography in a blood sample drawn 3 h after intake of a single oral 20-mg dose of omeprazole by 22 healthy subjects and five patients with newly diagnosed epilepsy. The procedure was repeated on the 4th day of 200 mg of ketoconazole intake (10 subjects), after 3 weeks of 150–200 mg twice-daily carbamazepine (five patients), and on the 6th day of 4 mg twice-daily tolterodine (12 subjects). Five subjects also took 100 mg and 50 mg of ketoconazole for 3 days before concomitant intake with omeprazole.Results The mean log10(omeprazole/omeprazole sulfone) ratio was 0.18 3 h after intake of omeprazole alone. After concomitant intake of ketoconazole, the corresponding value was 1.38 (p<0.001); after intake of carbamazepine it was −0.42 (p<0.05); and after tolterodine it was 0.29 (not significant). In the five subjects taking increasing doses of ketoconazole, the ratio was 0.11, 0.79, 1.2, and 1.5 after 0, 50, 100, and 200 mg of ketoconazole, respectively. The correlation between the metabolic ratios from the AUC_(0-6h) and from the single 3-h samples was very good, with a correlation coefficient of 0.92 (p<0.001).Conclusions A single blood sample taken 3 h after intake of 20 mg of omeprazole can be reliably used to phenotype for both CYP2C19 and CYP3A4 activity.Financial support was obtained from the National Network for Drug Development, within the Foundation for Strategic Research, Sweden.     

Oral bambuterol compared to inhaled salmeterol in patients with partially reversible chronic obstructive pulmonary disease

Objective: There is now good evidence that inhaled salmeterol is an effective agent in chronic obstructive pulmonary disease (COPD),but, at the present time, data on the effects of bambuterol, which is an oral tarbutaline pro-drug, in patients with COPD are scarce. Moreover, no comparative study between bambuterol and salmeterol in patients with chronic obstructive airway disorders has been published. The objective of this research was, consequently, to compare the efficacy and safety of 20 mg oral bambuterol and 50 μg inhaled salmeterol in patients with partially reversible COPD. Methods: The speed and length of bronchodilation with 20 mg bambuterol and 50 μg inhaled salmeterol were compared in 16 patients with partially reversible COPD. The investigation and designed as a double-blind, double-dummy, cross-over, placebo controlled and randomised study. Lung function (FEV₁, FVC) and systemic variables (subjective tremor, heart rate, blood pressure) were monitored prior to the administration of the drug and for 12 h after each agent on 3 non-consecutive days. Results: Inhalation of salmeterol induced a significant (P < 0.05) increase of lung function when compared with placebo. In addition, oral bambuterol elicited good bronchodilation, with its maximum slightly later than for salmeterol. The mean (±SE) AUC_0–12 hs for all patients were 3.134 1 ± 0.553 for salmeterol and 1963 1 ± 0.573 for bambuterol. Both AUC_0–12 h s were significantly greater than for placebo (P < 0.05), but there was no significant difference (P = 0.077) between the salmeterol and bambuterol AUC_0–12 hs. Bambuterol, but not salmeterol, caused tremor in four patients. Moreover, it induced a higher heart rate when compared with salmeterol at each considered time after the administration of the drug; differences after 9 and 12 h  were statistically significant (P < 0.05). Conclusion: Both oral bambuterol and inhaled salmeterol resulted in good bronchodilation in patients with stable COPD. However, bambuterol, but not salmeterol, caused tremor in several subjects and elicited a more pronounced tachycardia. Received: 11 May 1998 / Accepted in revised form: 13 September 1998     

Clinical efficacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository in patients with cancer pain

Objective: To compare the efficacy, safety and pharmacokinetics of a newly developed controlled- release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain. Methods: In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration–time curve (AUC)_0–12 h, peak plasma concentration (C_max), time to reach C_max (t_max), and C0 and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0–10 scale, while side effects and rescue medication were recorded. Results: Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC_0–12 h, t_max and C_max of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC_0–12 h and C_max of M6G, and AUC_0–12 h, C_max, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the t_max of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P=0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed. Conclusion: The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain. Received: 3 September 1999 / Accepted: 15 March 2000     

Effects of allicin on CYP2C19 and CYP3A4 activity in healthy volunteers with different <Emphasis Type="Italic">CYP2C19</Emphasis> genotypes

Objective  To investigate the interaction between allicin and omeprazole and to observe the effects of allicin on CYP2C19 and CYP3A4 activity in healthy Chinese male volunteers with different CYP2C19 genotypes. Methods  Eighteen subjects (six CYP2C19*1/CYP2C19*1, four CYP2C19*1/CYP2C19*2, two CYP2C19*1/ CYP2C19*3, and six CYP2C19*2/ CYP2C19*2) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or a 180 mg allicin capsule once daily for 14 consecutive days. The pharmacokinetics of omeprazole (20 mg orally on day 15) was determined for up to 12 h following administration by high-performance liquid chromatography. Results  In carriers of the CYP2C19*1/CYP2C19*1 and CYP2C19*1/CYP2C19*2 or *3 genotype, allicin treatment increased the peak plasma concentration (C_max) of omeprazole by 49.7 ± 7.2 (p < 0.001) and 54.2 ± 9.2% (p < 0.001), and increased the area under the plasma time–concentration curve ( ) of omeprazole by 48.1 ± 9.0 (p = 0.001) and 73.6 ± 26.7% (p < 0.001), respectively. The ratio of of 5-hydroxyomeprazole to omeprazole (a marker for CYP2C19 activity) decreased significantly (p < 0.001 and p = 0.001, respectively). However, no pharmacokinetic parameters were significantly changed by allicin in CYP2C19*2/CYP2C19*2. The C_max and of omeprazole sulfone were unchanged in all three genotypes. Conclusions  Allicin reduced the metabolism of omeprazole by inhibiting CYP2C19 activity in individuals with the CYP2C19*1/CYP2C19*1 and CYP2C19*1/CYP2C19*2 or *3 genotypes, but not in those with the CYP2C19*2/ CYP2C19*2 genotype. Allicin did not significantly affect the activity of CYP3A4 in all subjects.     

Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage – a pilot study

Objective The pharmacokinetics of nimodipine following enteral administration in the early phase after subarachnoid haemorrhage (SAH) has not been described. If a sufficient absorption could be achieved with enterally administered nimodipine, this would be more feasible dosage form and result in a significant reduction in pharmaceutical costs given that the parenteral formulation of nimodipine currently used is tenfold more expensive than the enteral formulation. Methods This was a pilot study in which 17 patients with aneurysmal SAH were randomly assigned to receive nimodipine within 24 h after initial bleeding either as an 60 mg tablet/suspension at 4-h intervals, or as a continuous intravenous infusion of 2 mg/h. Serum nimodipine concentrations were measured during the 4 h following the first dose, and at 24 and 72 h on a validated gas chromatography mass spectrometer (GC-MS). Results Nimodipine AUC values (expressed in μg min/ml) were lower in the eight SAH patients receiving enteral nimodipine [AUC_0–4 range: 0.13–5.4 (median: 0.32); AUC_24–28 range: 0.16–6.1 (0.71); AUC_72–76 range: 0.47–20.6 (1.9)] than in the nine patients receiving a continuous intravenous infusion of nimodipine [AUC_0–4 range: 2.4–4.9 (3.4), p = 0.059; AUC_24–28 range: 4.7–10.3 (7.3), p = 0.001; AUC_72–76 range: 3.4–8.6 (6.9), p = 0.001]. In three of five good-grade SAH patients receiving nimodipine tablets the AUC values were comparable to those of the intravenous administration, but in two good-grade patients with tablets and in all three poor-grade (Hunt&Hess, grade IV) SAH patients receiving the suspension, the rate and extent of nimodipine absorption was negligible. Conclusion This pilot study indicates that the rate and extent of nimopidine absorption following enteral administration in some acute SAH patients could be negligible, and this may particularly be the case in patients with a decreased level of consciousness.     

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     

Pharmacokinetics and bioequivalence evaluation of three commercial tablet formulations of mefloquine when given in combination with dihydroartemisinin in patients with acute uncomplicated falciparum malaria

Objective: To assess the pharmacokinetics and relative bioavailability/bioequivalence of three commercial tablet formulations of mefloquine, i.e. Lariam (reference formulation), Mephaquin 100 Lactab and Eloquin-250, when given sequentially after dihydroartemisinin in Thai patients with acute uncomplicated falciparum malaria. Methods: Twenty-nine Thai patients with acute uncomplicated falciparum malaria were randomised to receive an initial dose of 300 mg dihydroartemisinin, followed by 1250 mg mefloquine (at 24 h and 30 h after dihydroartemisinin) given as either Lariam (n=10 cases), Mephaquin (n=9 cases) or Eloquin-250 (n=10 cases). Serial blood samples were obtained up to day 42 after treatment with mefloquine. Mefloquine concentrations were determined in whole blood by means of ultraviolet high-performance liquid chromatography. The pharmacokinetic parameters of mefloquine were estimated using non-compartmental and compartmental analysis. Results: The three combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, nine patients (four and five cases in regimen containing Mephaquin 100 Lactab and Eloquin-250, respectively) had reappearance of parasitaemia during the follow-up period. Mefloquine from the three formulations showed significantly different pharmacokinetic and bioavailability metrics. Significantly lower peak plasma concentrations (C_max) and areas under the plasma concentration–time curve (AUC; AUC_0–48h, AUC_0–7days, and total AUC) were observed with Mephaquin 100 Lactab than with the other two formulations. Mean values for relative bioavailability of the test to standard products were 49.1% (Mephaquin 100 Lactab) and 72.4% (Eloquine-250). Based on the criteria set, the bioavailability of the two test products (Mephaquin 100 Lactab and Eloquine-250) was considered non-equivalent to the reference product with respect to the rate (t_max, C_max) and extent (AUC_0–48h, AUC_0–7days, total AUC) of mefloquine absorption. Received: 15 June 1999 / Accepted in revised form: 7 October 1999     

THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

The effect of omeprazole (2 mg kg⁻¹ i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg⁻¹) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial p_CO2, p_O2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration–time curve (AUC_0–180 ), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p<0·01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (C_max=156± 6·5 ng mL⁻¹ against 51±5·8 ng mL⁻¹ in control; p<0·05). AUC_0–180 was higher (p<0·05) after omeprazole treatment (18·6±1·4 μg mL⁻¹ min) than in control (6·8± 0·6 μg mL⁻¹ min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4·7±0·1 against 2·2±0·04) and continued increasing, being 6·4±0·1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect– (respiratory depression–) time curve (r=0·74; p<0·001). A relationship between plasma methadone levels at 120 min and gastric pH (r=0·92; p<0·001) was detected. A significant correlation between the area under the effect–time curve (0–120 min) and AUC_0–180 has been also observed (r=0·90; p<0·01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH 2 solution.     

The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose

Objective Induction of CYP3A by St. John’s wort (SJW) extracts with high hyperforin (HYF) content is well described. Since SJW products vary in the amount of HYF and other main constituents, the aim of the study was to evaluate the effect on CYP3A function of SJW preparations with a range from very low to high HYF content. Methods Forty-two male, healthy volunteers were randomized into six parallel SJW medication groups with varying composition especially with regard to HYF content. Midazolam plasma concentration profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. Results All SJW preparations tested resulted in a decrease in midazolam AUC, although the extent of the effect differed. The extract LI 160 (HYF 41 mg/day) decreased midazolam AUC_0–12h by 79.4% (95% CI −88.6; −70.1), which was significantly greater than the effect by any other medication (p<0.05). SJW powder tablets 2.7 g/day (HYF 12 mg/day) resulted in a midazolam AUC_0–12h decrease of 47.9% (95% CI −59.7;−36.2), while 2.7 g/day SJW powder tablets that were almost devoid of HYF (0.13 mg/day) reduced midazolam AUC_0–12h by only 21.1% (95% CI −33.9; −8.3). Considering all six SJW medications tested, the extent of midazolam AUC decrease correlated significantly with increasing HYF dose (r=−0.765, p<0.001), but not with hypericin dose (r=−0.067; p=0.673). Conclusion The extent of induction of CYP3A varies among St. John’s wort products and depends on hyperforin dose. The study was presented in part at the 2005 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Orlando, Florida, 2–6 March 2005. The study was started after approval by the ethics committee of the University of Rostock and was performed according to the national laws of Germany.