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P Workman

Publications and source records attributed to P Workman.

At least 217 records · Page 12Linked to original sources
PubMed1983

The role of dexamethasone in the modification of misonidazole pharmacokinetics.

A review of misonidazole pharmacokinetics in 83 consecutive patients treated for tumours other than glioma has shown that among patients not receiving enzyme-inducing agents the plasma elimination half life is lower in patients taking steroids. Such a difference is not seen if patients already taking enzyme inducers are given steroids. Five further patients with carcinoma of the lung, treated with radiation over a period of 3 weeks, have been studied in greater detail. Misonidazole, in oral dose of 1 gm-2, was given in conjunction with the first and last radiotherapy fractions, and dexamethasone, in a divided daily dose of 8 mg, was given throughout the radiation treatment, commencing after the first treatment. Misonidazole pharmacokinetics were studied at each administration. Following the dexamethasone treatment period there was a 25% reduction in misonidazole plasma elimination half life, a 24% reduction in plasma AUC0-00, and a 38% increase in 24 h urinary excretion (all changes being statistically significant--P less than 0.005). No changes were observed in the plasma AUC0-24 and urinary excretion of the major metabolite desmethylmisonidazole. Glomerular filtration rates in one patient, before and after treatment with dexamethasone, remained unchanged. These results suggest that the effect of dexamethasone on misonidazole kinetics is not related to an enhancement of demethylation.

Adult↗
PubMed1983

An investigation of the possibility of chemosensitization by clinically achievable concentrations of misonidazole.

Experiments have been carried out both in vitro and in vivo to examine the possibility of chemosensitization by misonidazole (MISO) at concentrations which are achievable in the clinic. Using multicellular tumour spheroids in vitro we found that a 16 h pre-incubation with 100 micrograms ml-1 MISO under hypoxic conditions led to a considerable enhancement of sensitivity to melphalan (MEL) but not to CCNU. Pre-incubation for 16 h under hypoxia alone also produced a degree of sensitization to MEL, but there was no effect of oxic pre-incubation with MISO. In vivo experiments using the KHT or RIF-1 tumours in C3H mice were designed so that repeated administration of MISO maintained blood concentrations of around 100 micrograms ml-1 for either 7 h or 16 h. For the 7 h regime, cytotoxic drugs were administered at the 4 h point. In most experiments the tumour response to MEL, cyclosphosphamide (CTX), chlorambucil or CCNU was no greater in mice receiving multiple MISO than in mice receiving multiple injections of a balanced salt solution. In the occasional experiment where there was an apparent increase in response, the effect was only small (dose modifying factor less than 1.5). For the 16 h regime the effect was studied of administering CTX (100 mg kg-1) at various times during the regime. There was a clear trend towards increased CTX response in mice receiving multiple MISO compared with controls. There was, however, no clear tendency for the effect to increase with length of MISO pre-exposure.

Animals↗
PubMed1983

The penetration of misonidazole and desmethylmisonidazole into brain tumours and other central nervous system tissues in man.

The concentration of drug after oral administration of 1 g misonidazole to patients undergoing neurosurgery has been studied in samples taken from intracerebral tumours, normal brain, cerebrospinal fluid and brain tumour cyst fluid. A total of 31 patients yielded samples at various times 2-8 h after drug administration. Results show a considerable range of tumour/plasma percentages but from about 2-5 h after drug administration this averaged between 65-80%. Normal brain and CSF showed similar good penetration but drug entry into cyst fluid was lower (30-50%). A further study with desmethylmisonidazole given to 11 additional patients showed a similar range of tumour penetration but lower concentrations in CSF and cyst fluid (10-20%). Low values were also seen in some but not all of the normal brain tissue samples. Necrotic tumour also had much lower concentrations than macroscopically viable tissue. These results are discussed in terms of their clinical relevance to sensitiser studies on patients with brain tumours with drugs of different lipophilicities.

Adolescent↗
PubMed1983

The role of microsomal enzyme inducers in the reduction of misonidazole neurotoxicity.

In a series of studies, we have shown that phenytoin, 300 mg daily for one week, produces consistent hepatic microsomal enzyme induction, resulting in a decrease of 25% in misonidazole half-life, without causing any toxicity per se. A longer period of administration gives only a slightly greater induction. Phenobarbitone in a daily dose of 90 mg causes a reduction of 18% and 23% in misonidazole half-life after 1 and 2 weeks' pre-treatment respectively, but is less suitable clinically because of its sedative effect. A further series of studies using phenytoin as the inducing agent has shown that, despite adequate enzyme induction and increased misonidazole metabolism, it is impossible to increase the total dose of misonidazole beyond the usually accepted value of 12 g/m2 because of unacceptable neuropathy (a rate of 50% at a dose of 14 g/m2 over three weeks). In single doses of above 3.0-4.0 g of misonidazole, severe nausea and vomiting are prominent, so that this side effect is a determining factor in the treatment fractionation. Audiometric studies show no correlation between the incidence of peripheral neuropathy and abnormal audiograms, and have no value in the early prediction of neurotoxicity. It seems that despite causing increased metabolism, enzyme induction does not protect against neurotoxicity and thus will not permit the use of higher doses of misonidazole for increased radiosensitisation.

Adult↗
PubMed1982

Effects of the xanthine oxidase inhibitor allopurinol on the renal clearance of nitroimidazoles.

We have investigated the effects of the xanthine oxidase inhibitor allopurinol on the pharmacokinetics of nitroimidazoles in mice and dogs. Studies in mice showed that at a dose of 32 mg/kg given 30-60 min before, allopurinol had little or no effect on the clearance of misonidazole (MISO) or of the more lipophilic analogue Ro 07-0913, but did increase the blood concentrations of the hydrophilic dealkylation product desmethylmisonidazole (DEMIS). In addition, the clearances of administered DEMIS and the even more hydrophilic analogue SR-2508 were markedly reduced. This dose of allopurinol also caused a considerable fall in the clearances of 51Cr-EDTA and 125I-iodohippurate, normally used to measure glomerular filtration rate and effective renal plasma flow respectively. These data are consistent with a model in which allopurinol inhibits the renal clearance of hydrophilic nitroimidazoles. This leads to an increase in the acute toxicity of DEMIS and, to a lesser extent, of MISO. However, lower doses of allopurinol did not change the pharmacokinetics of MISO or DEMIS. A five-day pretreatment regimen (32 mg/kg/day) followed by a 66-76 hr recovery period was also without effect, thus demonstrating that the inhibition was reversible. Investigations in the dog showed that oral doses of 10-20 mg/kg allopurinol caused no change in the clearance of either 51Cr-EDTA or DEMIS.

Allopurinol↗
PubMed1982

Structure/activity relationships for the enhancement by electron-affinic drugs of the anti-tumour effect of CCNU.

Using a regrowth-delay assay, we investigated structure/activity relationships for the enhancement by electron-affinic agents of the anti-tumour effect of the nitrosourea CCNU against the KHT sarcoma in C3H mice. A series of neutral 2-nitroimidazoles similar in electron affinity but varying in octanol/water partition coefficient (PC) over 4 orders of magnitude (0.016- greater than 200, Misonidazole = 0.43) were examined at a fixed dose of 2.5 mmol/kg. A parabolic (quadratic) dependence of activity on log PC was observed. Analogues more hydrophilic than misonidazole (MISO) were inactive as were those with very high PCs (greater than 20). Those with PC 0.43--20 were usually more active than MISO, some considerably so. The fairly lipophilic 5-nitroimidazoles nimorazole and metronidazole (METRO) had similar activity to MISO, despite their reduced electron affinity. Two basic 2-nitroimidazoles more efficient as radiosensitizers in vitro likewise showed activity comparable to MISO. We also investigated several agents more electron-affinic than MISO, including some non-nitro compounds. Most were inactive at maximum tolerated doses, but nitrofurazone showed reasonable activity. Sensitizer dose-response curves were obtained for MISO, METRO and two of the most effective agents, benznidazole (Ro 07-1051) and Ro 07-1902. The two latter agents were both considerably more active than MISO at low doses (0.1--0.9 mmol/kg). These studies indicate that the structural features of electron-affinic agents responsible for the enhancement of KHT tumour response to CCNU, are quite different from those affecting radiosensitization, lipophilicity being particularly important. The microsomal enzyme-inhibitor SKF 525A increased the anti-tumour effect of CCNU, suggesting inhibition of CCNU metabolism as one possible mechanism contributing to chemosensitization by lipophilic electron-affinic agents in mice.

Animals↗
PubMed1982

Response of a high-glucuronidase human tumour xenograft to aniline mustard.

The HT29R colonic adenocarcinoma xenograft has been shown to be rich in the enzyme beta-glucuronidase. Experiments in rodent systems have demonstrated a marked anti-tumour effect of the drug aniline mustard (AM) on tumours with high levels of this enzyme (e.g. the plasmacytomas PC5 and PC6). We have found that AM is no more effective than its analogue paramethyl aniline mustard (PMAM) or other alkylating agents against the HT29R xenograft. Amongst the possible explanations for this may be: (1) The wide shoulder on the cell-survival curve shown for exposure to alkylating agents of HT29R in vivo. (2) Lack of correlation between physiological availability of beta-glucuronidase and the high levels measured by the standard assay. (3) Increased beta-glucuronidase levels in host mouse marrow, making the latter potentially more susceptible to AM damage.

Adenocarcinoma↗
PubMed1982

Effect of misonidazole or metronidazole pretreatment on the response of the RIF-1 mouse sarcoma to melphalan, cyclophosphamide, chlorambucil and CCNU.

The effect has been studied of adding either misonidazole (MISO) or metronidazole (METRO) to cytotoxic drug treatment of C3H mice bearing the RIF-1 sarcoma. The nitroimidazoles were injected 30 min before the cytotoxic drugs at a dose of 2 . 5 mmol/kg. Both clonogenic-cell survival and growth delay were measured as indicators of tumour response and depression in WBC count and acute lethality were used to indicate normal-tissue response. For melphalan, neither pretreatment agent produced any change in tumor response. For cyclophosphamide, no change was produced by METRO but a minimal increase in tumour response occurred with MISO. An enhancement of cell killing by CCNU was seen with MISO pretreatment, but there was no increase in tumour growth delay. METRO, however, did not enhance tumour response by either endpoint. WBC depression by CCNU was not enhanced by MISO pretreatment, and there was no significant reduction in the acute LD50. This indicates a therapeutic advantage from the addition of MISO to CCNU in this model system. For chlorambucil, considerable enhancement of tumour response followed either MISO or METRO pretreatment (dose-modifying factors of 2 . 0 and 1 . 4 respectively). However, the modification by MISO of normal-tissue response to chlorambucil was also enhanced by about a factor of 2, with no therapeutic gain.

Animals↗
PubMed1981

Structure-pharmacokinetic relationships for misonidazole analogues in mice.

We have compared the mouse pharmacokinetics of six analogues of the hypoxic cell sensitizer misonidazole (MISO). The analogues were all uncharged and similar in redox potential, but widely different in octanol-water partition coefficient (range 0.026-1.5). Lipophilic analogues were cleared mainly by metabolism and non-linear elimination kinetics were seen at high doses. Hydrophilic analogues, including desmethylmisonidazole, SR-2508, and SR-2555, were removed principally by renal clearance exhibiting linear elimination kinetics. Lipophilic analogues were cleared more rapidly after hepatic microsomal enzyme induction by phenobarbitone, whereas the kinetics of hydrophilic analogues were unaffected. Low-dose clearance was similar for most of the analogues. But the hydrophilic SR-2555 was cleared twice as quickly as MISO, and the lipophilic Ro 07-0913 seven times faster than MISO. Plasma protein binding was low for all the analogues. The significance of these results for the predictive value of the mouse as a model for man is discussed.

Animals↗
PubMed1980

Dose-dependence and related studies on the pharmacokinetics of misonidazole and desmethylmisonidazole in mice.

An understanding of lipophilicity and pharmacokinetics is important in developing alternative radiosensitizers to misonidazole (MIS). Analogues more hydrophilic that MIS, including its O-demethylated metabolite DEMIS (Ro 05-9963), appear promising candidates. In vivo testing is usually carried out in mice, and the present paper reports dose-dependence and related studies on the comparative kinetics of MIS and DEMIS in this species. The data are consistent with a model in which MIS is eliminated mainly by metabolism, including demethylation to DEMIS, and saturable (non-linear) kinetics are exhibited. Apparent t 1/2 increased with dose. But DEMIS is eliminated mainly by renal clearance exhibiting first-order (linear) kinetics. PHenobarbitone reduced the t 1/2 and toxicity of MIS but not of DEMIS. SKF 525A increased the t 1/2 of MIS. The following were not responsible for the non-linear kinetics of MIS: short-term enzyme induction by MIS; potent enzyme inhibition by the product DEMIS; decrease in body temperature by MIS; injection volume; and protein binding. For both MIS and DEMIS peak blood concentrations were about 2-fold lower for IP than IV injection. The IP bioavailability of DEMIS (1.07 mmol/kg) was 100%, but that of MIS (1 mmol/kg) was 80%, suggesting some first-pass metabolism. Both MIS and DEMIS were absorbed more slowly and gave lower peak blood concentrations after IP injection in a large (40 ml/kg) as against a small (10 ml/kg) volume. Peak concentrations were lower for equimolar IP DEMIS, but this was less marked at lower doses. With both MIS and DEMIS, tumour/blood and brain/blood ratios were slightly increased at higher doses. Some kinetic differences were also observed between male and female mice. The above findings, particularly the major differences in elimination kinetics between MIS and DEMIS, should be considered in in vivo experiments with nitroimidazoles.

Animals↗
PubMed1980

Pharmacokinetic and tumour-penetration properties of the hypoxic cell radiosensitizer desmethylmisonidazole (Ro 05-Ro-9963) in dogs.

The hypoxic cell radiosensitizer desmethylmisonidazole (1-(2-nitroimidazol-1-yl)-2,3-propandiol; Ro 05-9963; DEMIS) was administered to 4 dogs at doses of 50 and 200 mg/kg by both oral and i.v. routes. The resulting plasma, cerebrospinal fluid and urinary concentrations were measured by HPLC analysis; various pharmacokinetic parameters were obtained and compared with similar data for the parent compound, misonidazole (MISO), in the dog.Because of its shorter half-life (2·1 h) the total tissue exposure for DEMIS was only half that for a similar dose of MISO, whereas peak plasma concentrations were 60% higher than those for MISO. Cerebrospinal fluid penetration by DEMIS was limited because of the drug's reduced lipophilicity, and the total cerebrospinal-fluid exposure to the drug during the first 5 h after drug administration was about half that previously recorded for MISO.Urinary excretion accounted for 75% of the i.v. dose of unchanged DEMIS, whilst less than 20% of MISO is excreted via this route.DEMIS was also administered to 6 dogs bearing spontaneous tumours at a dose of 150 mg/kg i.v., and the resulting concentrations were recorded in serial biopsies over a 5h period.Mean tumour/plasma ratios ranged between 56 and 90%, and were very similar to those previously observed for MISO in canine tumours. Peak DEMIS tumour concentrations, however, occurred rapidly after dosage (15-20 min) and were as much as twice those for MISO, although they declined rapidly from their initial concentration.We conclude in the light of the reduced tissue exposure, particularly of the nervous tissue, and the improved tumour concentrations, that DEMIS may prove to be a potentially less toxic alternative to MISO.

Animals↗
PubMed1980

Effects of local hyperthermia on the pharmacokinetics of misonidazole in the anaesthetized mouse.

The effects of sodium pentobarbitone anaesthesia, the presence of a tumour, and local hyperthermia to a tumour-bearing leg, on the pharmacokinetics of MISO in the mouse are reported. Analysis of MISO and its metabolite Ro 05-9963 was by high-performance liquid chromatography. The plasma kinetics of MISO were largely unaffected by any of these treatments, but hyperthermia substantially reduced tumour concentrations of the drug. The effects of tumour site and size on unheated-tumour drug concentrations were also studied, and an increase in tumour size was shown to decrease tumour MISO levels, but to different degrees according to whether implanted in the leg or flank. Uniformity of MISO distribution throughout heated and unheated tumours was examined, and levels were found to be constant within tumours. The presence of a temperature detector in heated tumours did not affect their drug concentration.

Abdomen↗
PubMed1980

Pharmacokinetics of hypoxic cell radiosensitizers: a review.

The comparative pharmacokinetics of various nitroimidazole radiosensitizers in different species are reviewed. Radiosensitization is dependent upon the tumor concentration at the time of radiotherapy, whereas host toxicity, including peripheral neuropathy, appears to be related to the tissue exposure or area under the curve (AUC). In contrast to in vitro structure-activity relationships, lipophilicity has a major effect on therapeutic ratio by influencing pharmacokinetics. Nitroimidazoles penetrate lipoid membranes by passive diffusion, the rate increasing with lipophilicity. Derivatives more hydrophilic than misonidazole (e.g., Ro 05-9963, SR-2508, and SR-2555) penetrate nervous tissues comparatively slowly, the corresponding AUC's are lower and they are generally less toxic. They are eliminated mainly by renal clearance, and also have shorter plasma t1/2's than misonidazole in the dog, but not in the mouse. The more lipophilic drugs are eliminated mainly by metabolism and their t1/2's are reduced by hepatic enzyme induction. Ro 07-0913, more lipophilic than misonidazole, has a shorter t1/2 in the mouse through more rapid metabolism to Ro 05-9963. Tumor penetration is independent of t1/2, at least over the range 1/2-20 hours, and also independent of partition coefficient over the range 0.026 to at least 1.5. The therapeutic ratio may be increased with drugs both more and less lipophilic than misonidazole. Most plasma data for intravenous radiosensitizers can be described by a two-compartment open model. But in the mouse, the kinetics of misonidazole are dose dependent with increasing apparent t1/2 and AUC at higher doses due to saturable Michaelis-Menten kinetics for metabolism.

Administration, Oral↗