Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog.

The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.

Pharmacokinetics and metabolism of the cholecystokinin antagonist dexloxiglumide in male human subjects.

1. Mean concentrations of total (14)C and of dexloxiglumide at the end of single 20-min infusion doses of (14)C-dexloxiglumide (200 mg) to four healthy male subjects were 18.5 microg eq x ml(-1) and 19.5 microg ml(-1) respectively. The mean plasma clearance (0.22 l h(-1) x kg(-1)) and mean volume of distribution (V(ss) = 0.18 l kg(-1)) were low. 2. Single oral doses of a solid formulation of (14)C-dexloxiglumide (200 mg) to the same subjects appeared to be rapidly and well absorbed. Mean peak plasma concentrations (C(max)) of total (14)C (2.8 microg eq x ml(-1)) and of dexloxiglumide (2.2 microg x ml(-1)) occurred at about 1.5 h. Systemic availabilities of the oral dose based on total (14)C and dexloxiglumide were 70 and 48%, respectively. Thus, a proportion of an oral dose was subjected to presystemic elimination and the absorbed dose mainly eliminated by metabolism. Binding of dexloxiglumide to plasma proteins was extensive (96.6-99.2%). 3. Total (14)C was excreted mainly in the faeces. Mass balance of (14)C excretion was almost complete within 7 days when a mean of > 93% of the dose had been recovered. After the intravenous (i.v.) dose, mean totals of 23.7 and 69.8% of the dose were excreted in urine and faeces, respectively, during 7 days, and 19.5 and 73.7% of the dose, respectively, after the oral dose. The data were consistent with biliary excretion and perhaps some enterohepatic circulation of conjugates of dexloxiglumide and at least one of its metabolites. 4. LC-MS/MS of urine extracts showed that dexloxiglumide was metabolized by oxidation and conjugation. The former included at least two metabolites formed by monohydroxylation in the N-(3-methoxypropyl) pentyl side chain, and O-demethylation of this side chain followed by subsequent oxidation of the resultant alcohol to the dicarboxylic acid. At least one glucuronide was also present in urine. The main components in faeces appeared to be dexloxiglumide and a dicarboxylic metabolite formed by O-demethylation followed by oxidation of the N-(3-methoxypropyl) side chain. Both compounds were identified as their corresponding methyl esters formed because acid and methanol were used in the extraction procedure. Dexloxiglumide and the dicarboxylic acid were presumably excreted in bile as the glucuronic acid conjugates.

Measurement of platinum in saliva of patients treated with cisplatin.

A procedure for the measurement of platinum (Pt) in the saliva of patients treated with cisplatin has been developed. The saliva is collected and solubilized in hyamine hydroxide before analysis by graphite furnace atomic absorption spectrometry using assay by standard additions. The method has an analytical detection limit of 0.025 microgram/mL and is precise, with coefficients of variation of 3-10.0% over a range of 0.05-2.0 micrograms/mL. Platinum was measured in saliva collected during an 8-h infusion of cisplatin from five patients, at the end of a 30-min infusion in nine, and 24 and 48 h later from a further 15 patients, all of whom were treated with cisplatin for squamous cell carcinoma of the neck. The platinum concentration in saliva taken at the end of a 30-min infusion was 0.27 +/- 0.23 microgram/mL (mean +/- 1 SD) but was below the detection limit of 0.025 microgram/mL at 24 and 48 h. After an 8-h infusion the salivary Pt was significantly less (0.12 +/- 0.04 microgram/mL; P < 0.05). The plasma Pt concentrations after 30-min and 8-h infusions were 2.98 +/- 1.03 and 2.54 +/- 0.59 micrograms/mL, respectively, and were not significantly different. The results indicate higher concentrations of free platinum in plasma after 30 min compared with an 8-h infusion. The monitoring of salivary concentrations of platinum may therefore provide a non-invasive way to study the unbound fraction of cisplatin in blood and facilitate optimization of cisplatin treatment.

Serial changes in serum vitamin K1, triglyceride, cholesterol, osteocalcin and 25-hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis.

Serum vitamin K1 concentrations were measured at presentation (just before surgery) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur (FON, n = 13) or total hip replacement for osteoarthritis of the hip (OA, n = 16). In comparison with healthy elderly volunteers (n = 25), serum vitamin K1 concentrations were significantly lower in both groups at presentation, and fell significantly within 24 h after surgery to concentrations approaching non-detectable, subsequently returning to pre-operative values within 3 weeks. Serum vitamin K1 tended to be lower in the fracture group both before and after operation, although calculation of a vitamin K1-triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group. Osteocalcin concentrations were similar and fell significantly after operation in both groups, returning to pre-operative levels within 7 days. No differences in the two forms of osteocalcin (carboxylated and undercarboxylated) were observed either before or after operation in either group. 25-Hydroxyvitamin D3 concentrations were not significantly different between the two groups at any time. Vitamin K1 status may be lower than desirable in certain groups of the elderly population, and supplementation should be considered as prophylactic therapy.

Cisplatin-albumin complex for treatment of cancer of the head and neck.

Many patients with cancer of the head and neck are unable to receive or continue treatment with cisplatin, which is nephrotoxic, because of poor renal function. We present here, however, the case of a patient who underwent conventional cisplatin therapy but who then had to be withdrawn from treatment because of renal toxicity despite having undergone partial remission. Treatment was then changed to cisplatin in the form of a cisplatin-albumin complex which is not nephrotoxic. The patient went on to a histologically confirmed complete response and we suggest that although the cisplatin-albumin complex may not be as effective as the conventional form of the drug it offers a possible form of treatment of patients with compromised renal function who could not otherwise be treated.

Phase I trial of a cisplatin-albumin complex for the treatment of cancer of the head and neck.

1. A phase I trial of a cisplatin-albumin complex for the treatment of end-stage squamous cell carcinoma of the head and neck is reported. The complex was prepared by overnight incubation of cisplatin with human albumin at 37 degrees C. This resulted in more than 98% of the drug being bound to protein at the start of treatment. The patients were either unable to continue with or had refused conventional therapy with cisplatin. 2. The trial began at a dose of 100 mg cisplatin m-2 and was increased in 25 mg m-2 increments to 650 mg m-2. Despite the absence of the customary protective measures of pre-hydration and anti-emetic treatment no serious toxicity was encountered. 3. Unbound plasma platinum concentrations were lower than after conventional cisplatin treatment but total plasma platinum and tumour platinum concentrations were much higher. Urinary excretion of platinum was low and the incidence of nephrotoxicity was greatly diminished. Two responses were seen (one complete and one partial) in 38 patients treated and the median survival time was 109 days, compared with 151 days for patients treated conventionally with cisplatin and 56 days for untreated patients. 4. The complex is not as effective as conventional cisplatin therapy but is much less toxic, offers improved quality of life during treatment and may prove to be of benefit in patients who could not otherwise be treated.

Failure of a 21-aminosteroid antioxidant to ameliorate cisplatin-induced nephrotoxicity.

1 Lazaroid (U74500A), a 21-aminosteroid antioxidant, was administered to rats at a dose of 10 mg kg-1 in an attempt to reduce the toxicity of cisplatin (5 mg kg-1). 2 No protective effect was apparent under the schedule used and, in contrast to other antioxidants and free-radical scavengers, U74500A offers no potential benefit in cisplatin treatment.

Disposition and tumour concentrations of platinum in hypoalbuminaemic patients after treatment with cisplatin for cancer of the head and neck.

1 Platinum concentrations in the tumour reached a peak of 3.8 +/- 1.5 micrograms g-1 wet weight tissue at the end of an 8 h intravenous infusion of cisplatin. The tumour concentrations of platinum were higher than the corresponding plasma concentrations (2.5 +/- 0.9 micrograms ml-1) and declined more slowly. 2 Patients with squamous carcinoma of the head and neck had a significantly shorter median survival time if they had low plasma albumin concentrations (less than 40 g l(-1) compared with patients in the normal range, 133 days and 768 days respectively (P less than 0.05) after treatment with cisplatin. 3 No changes in the pharmacokinetics of platinum were detected to account for this poor response of hypoalbuminaemic patients, but plasma albumin concentration was found to be negatively correlated with the first order elimination rate constant. 4 The cumulative urinary excretion of platinum in the first 24 h was not altered by lowered plasma albumin. 5 The concentration of platinum in the tumour did not correlate with the survival time of the patient, but was found to be correlated with the volume of distribution in the post-distributive phase.