Grapefruit juice interaction with oral budesonide: equal effect on immediate-release and delayed-release formulations.

Grapefruit juice (GFJ) inhibits CYP3A activity in the gut wall, thereby decreasing first-pass metabolism of CYP3A substrates. In this study be evaluated the influence of GFJ on the systemic availability of budesonide, a CYP3A-metabolised drug, both from an extended-release (ER) formulation and plain capsules. Eight healthy men participated in this open crossover study. Three mg budesonide as ER capsules or plain capsules was swallowed with or without previous intake of GFJ. Regular-strength GFJ 200 ml was given three times a day for four days. Budesonide was administered immediately after the first intake on the fourth day. A simultaneous intravenous low dose of deuterium-labelled budesonide enabled estimation of bioavailability and absence of hepatic inhibition. Concentrations of labelled and unlabelled budesonide in plasma were measured. GFJ did not affect systemic clearance of budesonide. Although absorption of the ER formulation to a great extent occurs from ileum and proximal colon where CYP3A activity is lower than in the upper small intestine, GFJ about doubled bioavailability after both ER and plain capsules. In conclusion, regular intake of grapefruit juice doubled the bioavailability of both plain and delayed-release budesonide, probably because of inhibition of all mucosal CYP3A activity.

Effect of erythromycin on the absorption of fexofenadine in the jejunum, ileum and colon determined using local intubation in healthy volunteers.

OBJECTIVE: To investigate the in vivo intestinal absorption mechanism(s) and systemic availability of fexofenadine in the jejunum, ileum and colon in humans. METHOD: A single dose of fexofenadine hydrochloride (60 mg as solution) was applied under fasting conditions, either alone or directly after a solution of erythromycin lactobionate (corresponding to a dose of 250 mg erythromycin), to the jejunum, ileum and colon in 6 healthy volunteers (3 male and 3 female) using a regional intubation dosing technology (Bioperm AB, Lund, Sweden). A total of 36 fexofenadine administrations were performed. The administration of fexofenadine to the specified location either alone or in combination with erythromycin was conducted in a randomized manner on 2 consecutive days with a 5-day washout period between doses. RESULTS: The plasma AUC for fexofenadine (mean +/- SEM) was higher (2.7-to 2.3-fold, p < 0.001) after application to the jejunum (1090 +/- 134 h x ng/ml) than to the ileum (404 +/- 102 h x ng/ml) or colon (476 +/- 212 h x ng/ml). No significant differences were found between application to the ileum and colon. The administration of erythromycin affected the absorption rate after jejunal application with a prolonged tmax from a median of 40 min (range 10-90 min) to a median of 3 hours (range 10-180 min) (p = 0.009). A change in tmax was not observed with application to the ileum and colon. The concomitant administration of erythromycin in the jejunum tended to increase the plasma AUC of fexofenadine from 1090 +/- 134 to 1750 +/- 305 h x ng/ml (p = 0.069). CONCLUSIONS: The systemic availability of fexofenadine was significantly higher after jejunal administration in accordance with a low permeability compound. The effects of erythromycin suggest that absorption of fexofenadine involves an uptake transport in addition to passive diffusion in the jejunum and predominantly passive diffusion in the ileum and colon.

Plasma protein binding of basic drugs. II. Importance of alpha 1-acid glycoprotein for interindividual variation.

The protein binding of two basic drugs, alprenolol and imipramine, and the acidic drug, naproxen, was determined in plasma obtained from 23 healthy subjects. A 2-fold variation was found between individuals in the free fraction of the two bases, while the range was even greater with naproxen. The free fraction correlated with the plasma concentration of alpha 1-acid glycoprotein for alprenolol (r = -0.75, p less than 0.001) and imipramine (r = -0.78, p less than 0.001), while there was no correlation for naproxen (r - 0.24, p greater than 0.1). This confirms recent experiments which showed that isolated alpha 1-acid glycoprotein avidly bound both alprenolol and imipramine. Drug binding, however, did not correlate with albumin concentration, although experiments with isolated albumin demonstrated its unusually high affinity for naproxen.

Renal excretion of cephapirin and cephaloridine: evidence for saturable tubular reabsorption.

Drug concentrations in plasma and urine were determined in 5 healthy subjects after intravenous infusion of 1 gm cephapirin and cephaloridine. Sampling of blood and urine was frequent and prolonged. Specimens were analyzed by high-pressure liquid chromatography (HPLC). Renal clearance of cephapirin decreased to less than 5% of control in all subjects when drug concentrations in plasma and urine declined. Cephaloridine clearance decreased to a lesser extent. Our findings suggest that, besides tubular secretion and glomerular filtration, a saturable and probably active tubular reabsorption is also involved in the renal handling of these two cephalosporins. The saturable reabsorption process was characterized by its Michaelis-Menten constant Km and its maximum transport capacity Tm.

Impaired plasma protein binding of phenytoin in uremia and displacement effect of salicylic acid.

The plasma protein binding of phenytoin (DPH) was studied by equilibrium dialysis at 37 degrees C in plasma from uremic patients and healthy subjects. Scatchard plot analyses demonstrated a decreased association constant Ka for the DPH-albumin interaction in the uremic plasma (mean 1.76 - 10(3) M-1 +/-SD 0.12 and a mean 4.10 - 10(3) M-1 +/- SD 0.24 in normal plasma). Studies on separated fractions of serum did not indicate any significant binding of DPH to proteins other than albumin. The nonlinear mathematical relationship between bound DPH and serum albumin could be linearized at low drug concentrations by plotting the ratio of bound/unbound DPH against albumin concentration. The displacement effect of salicylic acid at a concentration of 276 mug/ml (2mM) and DPH was considerable in plasma from normal subjects. In uremic plasma the effect was of much smaller magnitude.

Plasma protein binding of basic drugs. I. Selective displacement from alpha 1-acid glycoprotein by tris(2-butoxyethyl) phosphate.

The protein binding of a number of basic drugs has been shown to be inhibited when blood is collected in Vacutainer tubes. We found that the plasticizer tris(2-butoxyethyl) phosphate (TBEP), present in plasma collected in Vacutainers, was a potent inhibitor of alprenolol and imipramine protein binding. Its concentration in the plasma could quantitatively explain the displacement phenomenon. Alprenolol binding to a solution of a physiologic concentration (0.67 gm/L, 0.015 mM) of alpha 1-acid glycoprotein (orosomucoid) was decreased from 75% to 16% by addition of 10 microgram/ml (0.026 mM) of TBEP, while imipramine binding was decreased from 69% to 13%. Alprenolol and imipramine binding to albumin and lipoproteins was virtually unchanged by TBEP. Due to its selective effect on binding to alpha 1-acid glycoprotein, TBEP may be a useful tool for studying plasma protein binding of basic drugs.

Protein binding of salicylate in uremic and normal plasma.

Protein binding of salicylate was studied by equilibrium dialysis at 37 degrees C in plasma from uremic patients and healthy subjects. The protein binding was considerably lower in the uremic plasma at all salicylate concentrations studied (14 to 1,400 mug/ml). Scatchard plots of the data were computer-analyzed assuming binding to the classes of binding sites. According to this analysis, the binding to the class of primary binding sites was considerably decreased in the uremic plasma. In addition to the effect of the uremic state, the binding was considerably decreased at high therapeutic plasma levels and at low albumin levels. The combined effect of two or three of these factors may lead to unexpectedly high unbound fractions of salicylate, which should be considered in the monitoring of plasma salicylate levels in patients.

Techniques for plasma protein binding of demethylchlorimipramine.

The cerebrospinal fluid (CSF) and plasma levels of demethylchlorimipramine (DMCI) were determined during treatment of depression or obsessive-compulsive disorders with chlorimipramine. In 18 patients the mean CSF/plasma ratio of DMCI was 2.6% +/- 0.7 SD with fourfold variation (1.1% to 4.0%). In spite of this variation, the levels in CSF and plasma at steady state correlated closely (r = 0.91; p less than 0.001). With equilibrium dialysis for the determination of the protein binding of DMCI, a much higher free fraction was found in patients (8.0 +/- 1.6%) and in control subjects (8.2 +/- 1.4%). It was shown that part of the plasma binding capacity was lost during the incubation. Results obtained by ultrafiltration (3.9 +/- 1.0% unbound drug) were closer to the in vivo results, but this method also had disadvantages; much of the drug was absorbed on the ultrafiltration dialysis membrane. Our results suggest that there is a need for care in the selection of a technique for studies of drug protein binding.

Plasma levels and renal excretion of phenytoin and its metabolites in patients with renal failure.

Phenytoin (DPH) and its two major metabolites, conjugated and unconjugated 5-(4-hydroxyphenyl)-5-phenylhydantoin (4-OH-DPH), have been studied in plasma and urine to 4 healthy subjects and 3 uremic patients during two weeks on DPH, 0.1 gm daily. Only 0.4% to 1.2% of the dose was excreted as unchanged DPH. The DPH concentrations in urine were in the same range as calculated unbound levels of DPH in plasma in the normal subjects; 1% to 2% of the dose was excreted as unconjugated 4-OH-DPH in the normal subjects. In the uremic patients, renal clearance of this metabolite was reduced to one-sixth that percentage. Plasma concentrations rose to values twice as high as normal, indicating increased rate of glucuronidation. Urinary recovery of conjugated 4-OH-DPH in healthy subjects was 52% to 94%. Its renal clearance was close to glomerular filtration rate when corrected for protein binding, suggesting elimination by glomerular filtration rate when corrected for protein binding, suggesting elimination by glomerular filtration only. Plasma concentrations of conjugated 4-OH-DPH reached plateau levels around day 4 in normal subjects. In the uremic patients, plasma concentrations of this metabolite accumulated to levels 10 times normal, and after 15 days of medication plateau levels did not seem to have been reached.

Enprofylline kinetics in healthy subjects after single doses.

The kinetics of enprofylline, a novel antiasthmatic xanthine derivative, were studied. Eight healthy subjects received three different single enprofylline doses, 0.5, 1, and 1.5 mg/kg, injected as an infusion over 10 min. Plasma and urine levels of unchanged enprofylline were observed 3 to 7 and 21 to 24 hr after dosing. Plasma t 1/2 varied among individuals from 1.2 to 1.9 hr. Volume of distribution (V beta or area) and volume of distribution at steady state (V ss) averaged 0.57 and 0.511 X kg-1. Total clearance averaged 0.25 l X hr-1 X kg-1. Renal clearance ranged from 200 to 400 ml X min-1, indicating a large contribution by active tubular secretion. The mean recovery of unchanged drug in the urine was 89%. Thus, unlike theophylline, enprofylline was eliminated mainly by the kidney.

Concentration dependent plasma protein binding of salicylate in rheumatoid patients.

Acetylsalicylic acid in daily doses from 3 to 6g was prescribed to 8 patients with rheumatoid arthritis. Various assessments of clinical effect, as well as steady-state plasma concentrations and degree of plasma protein binding, were determined at each dose. The unbound fraction of salicylate increased with the dose, resulting in very high free concentrations of drug in some patients. No statistically significant relationship between total or unbound plasma concentration and the measurements of clinical efficacy were obtained. The marked increase with the dose in unbound salicylate concentration is interpreted as the result of the saturable elimination known to occur for this drug.

Two-fold interindividual variation in plasma protein binding of phenytoin in patients with epilepsy.

Plasma protein binding of phenytoin (diphenylhydantoin) in 63 epileptic patients was investigated with an ultrafiltration technique at room temperature using 14C-labelled phenytoin. A strong correlation was found between the total and the unbound drug concentration (r = 0.97, p less than 0.001). The unbound phenytoin fraction was 7.1 +/- 1.0% with a range of 4.9 to 10.2%. This variation is considerably less than that reported recently by different authors. Individual phenytoin binding was reproducible when the determination was repeated several weeks later. Salivary phenytoin concentrations in 33 epileptic patients were significantly correlated to the unbound (r = 0.83) and total concentrations (r = 0.82) of phenytoin in plasma. This study confirms that the clinical practice of monitoring total phenytoin plasma concentrations is sufficient, since the unbound phenytoin fraction has only a 2-fold interindividual variation in epileptic patients, provided that they do not suffer from renal or hepatic disease.

Pharmacokinetics and retrograde colonic spread of budesonide enemas in patients with distal ulcerative colitis.

METHODS: The retrograde spread of two budesonide enema formulations with different viscosities was investigated. The study design was open, randomized and two-period crossover. Three female and two male patients (age range: 35-45 years) with distal ulcerative colitis or proctitis participated. Both enema formulations contained a dose of 2 mg budesonide/100 mL. An unabsorbable radioactive marker (99mTc-labelled human serum albumin microcolloid) was added to the enema just before administration. All doses were given in the evening with the patients lying in a supine position during the whole investigation. The intestinal spread was followed for 8 h using scintigraphic imaging. Plasma samples for budesonide assay were taken during the 12 h after administration of the low viscosity enema. RESULTS: Budesonide plasma levels were measurable for up to 4-6 h. Cmax was 2.5 nmol/L (range: 0.9-4.5 nmol/L) and was attained in 1.5 h (range 1-3 h). The patients had no difficulty in retaining the enemas. There was a statistically significant difference in spread between the low and high viscosity enema. The low viscosity enema spread over an area situated between the rectum and the splenic flexure. The spread occurred mainly in the first 15 min after administration. In contrast, the high viscosity enema, in most cases, spread only over a minor part of this area and the rate and extent of spreading was also more variable with this formulation. CONCLUSION: The spread of a low viscosity enema appears to be well suited for the treatment of proctitis and distal colitis.

The role of P-glycoprotein in limiting intestinal regional absorption of digoxin in rats.

The objective of this work was to study the role of regional intestinal efflux activity of P-glycoprotein (Pgp) in situ in anesthetized rats in limiting the absorption of digoxin. A 10-cm portion of duodenum or jejunum, or 5-cm of colon was perfused single-pass with saline containing [(3)H]digoxin while the appearance of radioactivity in the blood was measured. Verapamil in the perfusate was used as a modulator of Pgp in the intestinal mucosa. Net water absorption, mucosal integrity, and intestinal motility of the isolated segment were monitored, as well as heart rate and blood pressure. Excretion of i.v. administered unlabelled digoxin, 1 mg/kg, into the intestine while perfusing the duodenum-proximal jejunum region, was studied for comparison. At a perfusate concentration of 1 mM, verapamil caused a dramatic increase in [(3)H]digoxin absorption rate from duodenum and jejunum, while the effect in colon was insignificant. At concentrations of 0.1, 1, and 2.5 mM in the duodenal perfusate, verapamil increased the absorption rate of [(3)H]digoxin in a dose-dependent manner. The lowest concentration almost doubled the rate without having any significant effects on the cardiovascular system, intestinal motility, or net absorption of water. The excretion rate of unlabelled digoxin from the blood into the gut lumen was found to be halved in the presence of 0.5 mM verapamil in the perfusate. Absorption rate of [(3)H]digoxin in the rat is likely limited by Pgp-mediated efflux. The data indicate that Pgp plays an important role for digoxin efflux in the small intestine only.

A dose-finding study with a novel water-soluble formulation of paclitaxel for the treatment of malignant high-grade solid tumours in dogs.

A new formulation of water-soluble paclitaxel (Paccal® Vet) has been developed for canine cancer patients, without the need for pre-medication (traditionally required in non-water-soluble paclitaxel formulations). The objective of the study was to determine a clinically safe and efficacious dose of Paccal Vet and to estimate progression-free and overall survival and to evaluate single-dose pharmacokinetics in tumour-bearing dogs. A positive risk:benefit ratio was established for Paccal Vet administered at 150 mg m(-2) intravenous (IV) for three or more treatment cycles. Preliminary efficacy was demonstrated by best objective response rate (86%), median time to response (14 days) and median progression-free survival (131 days). Paccal Vet was associated with expected adverse events (AE) (e.g. myelosuppression), however the majority were transient, clinically silent and manageable. This is the first clinical report of a water-soluble formulation of paclitaxel suggesting successful administration and being safely used without pre-medication in dogs.