Effects of dopamine on veins in humans: comparison with noradrenaline and influence of age

Objective: To compare the venoconstricting effect of dopamine with that of noradrenaline and to investigate the influence of age on the responsiveness to dopamine in human subjects. Methods: In eight young and eight elderly male subjects, increasing doses of dopamine or noradrenaline were infused into a dorsal hand vein and its diameter was measured using a linear variable differential transformer. Results: There was no significant difference between the maximum venoconstriction (E_max) for dopamine and that for noradrenaline. The infusion rate to induce 50% of E_max (ED₅₀) for dopamine in the young and elderly subjects was 363 ng · min⁻¹ and 352 ng · min⁻¹, and the ED₅₀ for noradrenaline was 40.7 ng · min⁻¹ and 43.8 ng · min⁻¹, respectively. Neither in the E_max nor in the ED₅₀ for these drugs were there significant differences between the young and elderly subjects. Conclusion: The venoconstricting effect of dopamine is 5–20 times less than that of noradrenaline, and aging does not influence the responsiveness to dopamine and noradrenaline in human subjects. Received: 29 August 1997 / Accepted in revised form: 5 February 1998     

Bayesian pharmacokinetic estimation of vinorelbine in non-small-cell lung cancer patients

Objective: To develop a population pharmacokinetics of vinorelbine in a population of non-small-cell lung cancer (NSCLC) patients using a Bayesian estimation in order to calculate for any further patient, individual pharmacokinetic parameters from few blood samples. Methods: Vinorelbine was given by a 15-min infusion (30 mg · m⁻²) to eight patients with NSCLC. Its serum concentration was determined by HPLC and its pharmacokinetics was described by a three-compartment open model with elimination from the central compartment. Volume of the central compartment (V₁) and rate constants (k₁₀, k₁₂, k₂₁, k₁₃, k₃₁) were selected as population pharmacokinetic parameters and computed by non-linear regression (two-step approach) from 14 to 18 concentration measurements per course. Subsequently, these parameters were used by the Bayesian estimator to calculate individual pharmacokinetics from only 2 or 3 measured concentrations. Results: The population mean values (CV%) of V₁, k₁₀, k₁₂, k₂₁, k₁₃, k₃₁, CL, t _1/2 were respectively 21 l (55%), 3.2 h⁻¹ (29%), 7.7 h⁻¹ (74%), 1.3 h⁻¹ (67%), 4.7 h⁻¹ (53%), 0.04 h⁻¹ (20%), 57 l · h⁻¹ (31%) and 43 h (36%). The comparison of results obtained from the Bayesian estimator and from the three-compartment model showed that CL and t _1/2 were well predicted (relative deviation: ±12 to 22%) by the Bayesian method using only two blood samples. Conclusion: We demonstrated that Bayesian estimation allows, at minimal cost and minimal disturbance for the patient, the determination of several vinorelbine pharmacokinetic parameters and therefore dose adaptation from as few as two drug concentrations, measured at 6 h and 24 h after infusion. Received: 4 July 1997 / Accepted in revised form: 15 November 1997     

Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole

Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml⁻¹, the mean C_max was 0.14 vs 0.31 μg · ml⁻¹and the mean t_max was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola. Received: 4 November 1996 / Accepted in revised form: 21 January 1997     

Variability of morphine disposition during long-term subcutaneous infusion in terminally ill cancer patients

Objective: To study the plasma concentrations of morphine and its glucuronides to assess the intra- and interindividual variability of the disposition of morphine administered by subcutaneous infusion in cancer patients. Methods: Blood samples were taken repeatedly in eight patients with severe cancer pain who were being treated with morphine (60–3000 mg per day) via chronic (8–160 days) subcutaneous infusion. Venous blood samples were collected at least weekly and, when possible, on 3 consecutive days after dose adaptation or any other major change in the patients' treatment. Concentrations of morphine and its glucuronides in plasma were measured after solid-phase extraction using a validated high-performance liquid chromatography assay. The stability of the morphine solutions was determined by repeated measurement of the concentrations of morphine and its degradation products in the solutions. Results: The morphine concentration in the infusion solutions remained unchanged during storage and infusion. The plasma concentrations of morphine and its glucuronides were within the ranges reported in the literature. There was, as expected, a large interindividual variability: from patient to patient, the mean of the normalised plasma concentrations ranged from 0.3 ng · ml⁻¹ · mg⁻¹ to 0.8 ng · ml⁻¹ · mg⁻¹ for morphine, from 1.0 ng · ml⁻¹ · mg⁻¹ to 3.1 ng · ml⁻¹ · mg⁻¹ for morphine-6-glucuronide and from 6.8 ng · ml⁻¹ · mg⁻¹ to 24.3 ng · ml⁻¹ · mg⁻¹ for morphine-3-glucuronide. Intraindividual variability was also important. The residual standard deviation of the mean normalised plasma concentrations calculated for each patient ranged from 26% to 56% for morphine, from 20% to 51% for morphine-6-glucuronide and from 20% to 49% for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found. Conclusion: During subcutaneous infusion of morphine, there is a large intra- and interindividual variability of the morphine disposition which could be of clinical relevance. Received: 5 August 1997 / Accepted in revised form: 8 October 1997     

Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery

   Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg⁻¹ sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg⁻¹ · min⁻¹, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min⁻¹ · kg⁻¹), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg⁻¹) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean C_max values of 421 (group I), 125 (group II), and 53 (group III) ng · ml⁻¹ and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg⁻¹ tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate. Received: 23 August 1995 / Accepted in revised form: 19 August 1996     

Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment

Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. Methods: Subjects with creatinine clearances (C_Cr) ranging from 0 to 213 ml · min⁻¹ received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal E_max model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min⁻¹, correlated with C_PAH (r ² = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC₅₀), maximal response (E_max), or basal response (E₀) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects. Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when C_Cr<50 ml · min⁻¹) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when C_Cr<10 ml · min⁻¹) to avoid therapeutic failure while remaining within the wide margin of safety for this drug. Received: 10 September 1996 / Accepted in revised form: 7 December 1996     

Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation

Objective: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/− cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated. Results: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The k_M value for the CYP3A4 expressed in the cells was 69.7 μmol · l⁻¹, and the V_max was 4.87 pmol · min⁻¹ · pmol⁻¹ P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a k_i value of 24.9 and 1390 μmol · l⁻¹, respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a k_i value of 4.3 μmol · l⁻¹. Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 μmol · l⁻¹, whereas higher concentrations of the compound (>10 μmol · l⁻¹) inhibited the hydroxylase activity. Conclusion: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity. Received: 10 April 1997 / Accepted in revised form: 16 December 1997     

Renal effects of nicardipine,a calcium antagonist,in hypertensive type 2 (non-insulin-dependent) diabetic patients with and without nephropathy

Summary The renal effects of oral maintenance doses of nicardipine 60–120 mg/day have been studied in 18 hypertensive patients with Type 2 (non-insulin-dependent) diabetes mellitus: 6 with normoalbuminuria (urinary albumin excretion rate, AER <20 μg · min⁻¹, Group A); 6 with incipient nephropathy, (AER 20–200 μg · min⁻¹, Group B); and 6 with overt nephropathy (AER >200 μg · min⁻¹, Group C). Treatment for 4 weeks significantly lowered the systolic and diastolic blood pressures and reduced total renal vascular resistance in all three groups. Nicardipine increased renal blood flow significantly in Group C and slightly in Group B, and had no effect in Group A. Glomerular filtration rate remained unchanged in all three groups. It significantly reduced AER and the fractional clearance of albumin in Group B, whereas AER in Groups A and C was not altered. Plasma renin activity, aldosterone concentration, osmotic pressure, serum total protein and albumin concentrations and haemoglobin A_1c level were similar in the control and nicardipine phases in all three groups. The results suggest that nicardipine may preserve renal function whilst having a concomitant hypotensive action in hypertensive Type 2 diabetic patients with normoalbuminuria and incipient nephropathy, and that the drug may improve renal blood flow in patients with overt nephropathy. The effect of the drug on urinary albumin excretion may deserve further investigation.     

Catalytic and Toxicity Mechanisms of Secretory Phospholipases A2

Abstract

Secretory phospholipases A₂ (sPLA₂s) are classified into two groups, Groups I and II, according to differences in the polypeptide-chain length and intramolecular disulfide bondings. We have performed the enzyme kinetic experiments on several Group I and II PLA₂s. The results suggested that the α-amino groups of Group I PLA₂s participated significantly in the catalysis and in the p-bromophenacyl bromide reaction but that those of Group II PLA₂s did not. It was also suggested that the substrate binding to Group I PLA₂s was practically independent of the Ca²⁺ binding to the enzymes, whereas that to Group II enzymes was Ca²⁺ dependent. We clarified for the first time these differences between Group I and II PLA₂s in terms of the catalytic mechanism.

Snake venom PLA₂s often display toxic (pharmacological) activities in addition to their primary catalytic function. Despite the differences in their ability to induce various toxic effects, these enzymes share high homology in their amino acid sequences. The distinct functional differences in the ability to induce various toxic effects among venom PLA₂s cannot be easily correlated with their structural differences. Numerous studies on the structure-function relationship have suggested the presence of separate toxic sites on the PLA₂ molecules that are responsible for their toxicity. It was also suggested that the selective binding of toxic PLA₂s to specific targets (receptors) could play a crucial role in their mechanism of action.     

Kinetics of interconversion of sulphamethoxydiazine crystal forms

A quantitative Nujol mull technique is described for the determination of sulphamethoxydiazine crystal forms in mixtures, so that the rates of their interconversion may be determined. The technique is applied to the transformations taking place in the more thermo-dynamically active as well as biologically available crystal form (Form II). Kinetic parameters indicate a highly temperature dependent transformation (E_a ? 100 kcal mol^?1; 418·6 kJ mol^?1) of Form II to the more stable Form I. Suspension in water results in a much faster transformation of Form II (E_a ? 20 kcal mol^?1; 83·7 kJ mol^?1, t_1/2 ? 15 min) to the water-stable Form III. Water and water vapour are shown to be important factors in the transformation of Form II at room temperature.     

The Effects of the Non-ionic Detergent Tween 80 on Hepatic Microsomal Hydroxylation

1. Effects of the non-ionic detergent Tween 80 on hamster liver microsomal components and on various reactions, including biphenyl hydroxylation, have been studied. Tween 80 competitively inhibited both 2- and 4-hydroxylation of biphenyl, with K_i values of 4·9 and 4·1 mM. The apparent kinetic constants corrected for the inhibitory effect of 2·9 mM Tween 80 (the concn. routinely used) were for 2-hydroxylation: K_m = 0·47mM, V_max = 2·2 nmol min/mg; and for 4-hydroxylation: K_m= 0·14 mM, V_max = 3·5 nmol/min/mg.

2. The type I spectrally apparent interaction of biphenyl with liver microsomes (K_s = 0·23 mM; δE_max = 8·2 E/2?mg protein) was also competitively inhibited by Tween 80 (K_i = 1·1 mM), itself an apparently type I substrate.

3. Tween 80 (9·5 mM) activated aniline 4-hydroxylation. The type II spectrally obvious interaction between aniline and microsomes was not affected by Tween 80.

4. Tween 80 and biphenyl together enhanced NADPH-cytochrome c reduction whereas Tween 80 and aniline together had no effect. Tween 80 did not affect the stability of cytochrome P—450 in microsomal suspensions over a 5?min period.

5. Results are discussed in terms of differences between biphenyl 2- and 4-hydroxylation systems, between type I and II substrate-enzyme complexes, and in terms of the relevance of spectral interactions to aryl hydroxylations.     

Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function

Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound. Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A >60 nl · min⁻¹ · 1.73 m⁻², group B 30–60 ml · min⁻¹ · 1.73 m⁻² and group C 15–30 ml · min⁻¹ · 1.73 m⁻²). Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUC_inf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline. Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment. Received: 3 August 1998 / Accepted in revised form: 19 October 1998     

The effect of pre-induction clonidine on platelet aggregation during minor surgery

Objective: This paper reports the results of a prospective randomized double-blind trial on the effects of pre-operative clonidine on platelet aggregation. Methods: Thirty adult (ASA I–II) patients undergoing elective minor orthopaedic surgery were randomly allocated into three groups of ten patients each. In group I clonidine 2 μg · kg⁻¹, in group II clonidine 4 μg · kg⁻¹ and in group III saline placebo was administered intravenously before the induction of anaesthesia. Anaesthesia was induced with propofol and vecuronium and maintained with halothane-nitrous oxide. Platelet counts and aggregation tests were performed before (t₀) and 1 h (t₁) and 24 h (t₂₄) after administration of the study drug. Results: Changes in platelet counts among the groups and values over time were not significant. Both maximum rate and intensity of collagen-induced aggregation in both clonidine groups and maximum intensity of adenosine 5′-diphosphate (ADP)-induced aggregation in the high-dose clonidine group increased significantly at t₁. However, all these increases in aggregation were within the normal ranges. Conclusion: The effects of both low and high doses of clonidine on platelet aggregation appeared to be minor, and we did not observe any increases above the normal ranges. Received: 16 December 1997 / Accepted in revised form: 9 May 1998     

Effect of prostaglandin E1 on pulmonary hypertension after protamine injection during cardiac surgery

Background: The effects of prostaglandin E₁ on pulmonary hypertension were assessed after protamine injection at the end of cardiopulmonary bypass during cardiac surgery. Methods: Ten patients scheduled for cardiac surgery presented with pulmonary hypertension (mean pulmonary artery pressure greater than 30 mmHg) after protamine injection and were treated by infusion of 0.02 μg · kg⁻¹ · min⁻¹ prostaglandin E₁. Hemodynamic measurements were made on occasions after cardiopulmonary bypass. Prostaglandin E₁ decreased pulmonary artery pressure, pulmonary vascular resistance, right ventricular stroke work index and pulmonary vascular resistance/systemic vascular resistance ratio, but did not change blood pressure, systemic vascular resistance, left ventricular stroke work index or cardiac output. Conclusion: Prostaglandin E₁ normalized pulmonary hypertension after protamine injection, but did not change arterial blood pressure and cardiac output. Received: 22 August 1997 / Accepted in revised form: 30 October 1997     

Involvement of multiple cytochrome P450 isoforms in naproxen O-demethylation

Objective: A series of studies was undertaken to determine the cytochrome P450 isoform(s) involved in naproxen demethylation and whether this included the same isoforms reported to be involved in the metabolism of other NSAIDs. Methods: (S)-Naproxen was incubated with human liver microsomes in the presence of a NADPH-generating system and the formation of desmethylnaproxen was measured by high-performance liquid chromatography (HPLC). To further clarify the specific isoforms involved, experiments were conducted with preparations expressing only a single P450 isoform (vaccinia virus-expressed cells and microsomes derived from a lymphoblastoid cell line, each transfected with specific P450 cDNAs) as well as inhibition studies using human liver microsomes and putative specific P450 inhibitors. Results: In human liver microsomes (n=7), desmethylnaproxen formation was observed with a mean k_M of 92 (21) μmol · l⁻¹, V_max of 538 pmol · min⁻¹ · mg⁻¹ protein and C_int2 (reflective of a second binding site) of 0.36 μl · min⁻¹ · mg⁻¹ protein. This C_int2 term was added since Eadie-Scatchard analysis suggested the involvement of more than one enzyme. Studies using putative specific P450 inhibitors demonstrated inhibition of this␣reaction by sulfaphenazole, (apparent Ki= 1.6 μmol · l⁻¹), warfarin (apparent Ki=27 μmol · l⁻¹), piroxicam (apparent Ki=23 μmol · l⁻¹) and tolbutamide (apparent Ki=128 μmol · l⁻¹). No effect was observed when α-naphthoflavone and troleandomycin were employed as inhibitors, but reaction with furafylline produced, on average, a maximum inhibition of 23%. At a naproxen concentration of 150 μmol · l⁻¹, formation of desmethylnaproxen was observed in cells expressing P450 1A2, 2C8, 2C9 and its allelic variant 2C9R144C. To further characterize these reactions, saturation kinetics experiments were conducted for the P450s 1A2, 2C8 and 2C9. The k_M and V_max for P450 1A2 were 189.5 μmol · l⁻¹ and 7.3 pmol · min⁻¹ · pmol⁻¹ P450, respectively. Likewise, estimates of k_M and V_max for P450 2C9 were 340.5 μmol · l⁻¹ and 41.4 pmol · min⁻¹ · pmol⁻¹ P450, respectively. Reliable estimates of k_M and V_max could not be made for P450 2C8 due to the nonsaturable nature of the process over the concentration range studied. Conclusion: Multiple cytochrome P450 isoforms (P450 1A2, 2C8 and 2C9) appear to be involved in naproxen demethylation, although 2C9 appears to be the predominant form. Received: 16 September 1996 / Accepted in revised form: 20 December 1996     

Combination therapy in hypertension

Summary The acute hypotensive effect of captopril 25 mg was investigated in 26 hypertensive patients (11 with essential and 15 with renal arterial disease). Intra-arterial blood pressure was recorded continuously and arterial blood was sampled for renin, angiotensin I and II, aldosterone, kininase II, catecholamines and prostaglandins. Captopril led to an increase in plasma renin activity, active and total plasma renin concentration and angiotensin I, a decrease in plasma kininase II activity, angiotensin II, aldosterone, prostaglandins E₂ and F_2* and no change in plasma (nor)adrenaline, dopamine and inactive renin concentration. The hypotensive effect of captopril was related to the changes in plasma angiotensin II level and inversely to the change in prostaglandin E₂; the correlation coefficients were low, respectively 0.61 and −0.44. It is likely that the acute hypotensive effect of captopril to some extent is related to changes in plasma angiotensin II and in prostaglandins E₂ and F_2*. There is no evidence for a role of the adrenergic systems in the hypotensive response.     

Kinetics of ceftazidime during plasmapheresis

Summary The influence of plasmapheresis (PA) on the elimination kinetics of ceftazidime (Cef) has been investigated. A single dose of Cef was administered intravenously to 11 patients with autoimmune diseases and varying degrees of renal impairment (Group I CL_CR<50 ml/min, Group II CL_CR>50 ml/min).In Groups I and II the mean total clearance of Cef (CL) was 30 and 116 ml/min^–1, respectively. The elimination half-life (t_1\2) and the volume of distribution (V) were significantly higher in Group I than in Group II (11.9 vs 2.0 h, 27.1 vs 18.5 l). PA had no influence on the plasma level-time profile of Cef. The amount of Cef recovered from separated plasma accounted for only 2 to 9% of the administered dose, being particularly low in patients with normal renal function (4.6%).Thus, since elimination of Cef via PA is negligible, dosage calculations should be based solely on renal function.     

Determination of the relative bioavailability of nedocromil sodium to the lung following inhalation using urinary excretion

Objective: To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods: Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses were compared. Results: Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin with cimetidine. Mean values for C_max (the maximum concentration) were 5.11 ng · eq · ml⁻¹ and 4.54 ng eq · ml⁻¹, for t_max (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC_0–24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq · h · ml⁻¹ and 58.5 ng eq · h · ml⁻¹, and for t_1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change from baseline for total cholesterol were −29.5% and −29.9%, for low-density lipoprotein (LDL) cholesterol −41.0% and −42.6%, for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides −33.8% and −25.8%, respectively. Conclusions: The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced by coadministration of cimetidine. Received: 17 February 1997 / Accepted in revised form: 3 November 1997     

Ventilation,CO2 Production,and CO2 Exposure Effects in Conscious,Restrained CF-1 Mice

Abstract: Respiratory rate (f), tidal volume (V_T) and carbon dioxide production (V_ECO₂) were measured in restrained, conscious CF-1 mice. Mean f ± S.D. and mean V_T ± S.D. were 270 ± 8 breaths/min. and 0.123 ± 0.024 ml (STPD) for male, and 274 ± 15 breaths/min. and 0.115 ± 0.023 ml (STPD) for female mice, respectively. V_EO₂ was obtained from a rebreathing (closed loop) system. The maximum V_ECO₂ (STPD) amounted to 95.5 ± 15.4 ml/(kg min.) in males and to 72.7 ± 4.2 ml/(kg min.) in females. The CO₂ concentration in the closed loop system increased slowly during a 30 min. rebreathing period and reached a concentration of about 2.7%. No effect was seen on f and on V_T. Dynamic (abrupt) exposure up to 10.3% CO₂ had no effect on f in male mice, whereas V_T increased from 112% (2.3% CO₂) to 181% (10.3% CO₂). The estimated O₂ concentrations decreased from 20.5% to 18.7% with increasing CO₂ exposure. The equivalent CO₂ experiments with O₂ kept at 16% by N₂ administration showed that the lower O₂ concentration added an additional drive on the respiratory centre.     

The pharmacokinetics of methotrexate after intravenous administration of methotrexate-loaded proliposomes to rats

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX-loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg^?1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (C_p), the area under the plasma concentration-time curve (AUC, 639 versus 913 μg min mL^?1), the terminal half-life (t_1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (V_ss, 98.1 versus 2800 mL kg^?1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min^?1 kg^?1), renal clearance (CL_R, 4.49 versus 2.78 mL min^?1 kg^?1), non-renal clearance (CL_NR, 7.50 versus 5.99 mL min^?1kg^?1), and the amount of MTX excreted in urine (X_u, 808 versus 685 μg, p < 0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX-loaded liposomes (formed immediately after hydration of MTX-loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT and V_ss from treatment II), and MTX is slowly released from MTX-loaded liposomes (higher t_1/2 from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higher C_p and AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such as t_1/2, MRT, and V_ss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX-loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX-loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX-loaded proliposomes when incubated with phosphate-buffered saline (PBS), rat plasma, or rat liver homogenate.