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Biomedical subjects

J B Houston

Publications and source records attributed to J B Houston.

At least 73 records · Page 4Linked to original sources
PubMed1988

Comparison of two azole antifungal drugs, ketoconazole, and fluconazole, as modifiers of rat hepatic monooxygenase activity.

The mechanism of action of azole antifungal agents is believed to involve inhibition of fungal cytochrome P-450, and, therefore, an investigation of the interaction of these drugs with mammalian cytochrome P-450 systems should provide some indication of their selectivity as antifungal agents. The ability of ketoconazole and fluconazole, the latter representing a new generation of triazole antifungal agents, to modify rat mixed function oxidase activity has been investigated in vitro with hepatic microsomes and in vivo using a N-methyl-[14C] antipyrine breath test. As a measure of selectivity the results have been compared with antifungal potency. Ketoconazole is more potent than fluconazole by an order of magnitude in inhibiting metabolism by O-dealkylation of ethoxycoumarin, methoxycoumarin and ethoxyresorufin (IC50 values of 6, 5 and 130 microM for ketoconazole respectively). The effects on the regio- and stereospecific hydroxylation of [14C] testosterone were also measured; the IC50 values for inhibition of total testosterone metabolism were 0.1 mM and greater than 3 mM for ketoconazole and fluconazole respectively. Marked selectivity differences were observed for the two drugs as indicated by ketoconazole being a potent inhibitor of 7 alpha-hydroxylation of testosterone (IC50 20 microM) while fluconazole did not inhibit this activity at 3 mM. In vivo investigations using a range of doses confirmed their ranking for inhibitory potency; the ED50 values for maximum demethylation rate were 17 mumol/kg and greater than 60 mumol/kg for ketoconazole and fluconazole respectively. Thus fluconazole has a lower propensity to interact with rat hepatic cytochrome P-450 and can be considered a more selective antifungal agent as its in vivo antifungal potency is an order of magnitude greater than ketoconazole.

Animals↗
PubMed1988

Kinetics of disposition of xenobiotics and their metabolites.

The principles of pharmacokinetics, which have evolved over the last quarter of a century and are now regarded as a major tool in quantifying and rationalizing drug action, are outlined. These are presented within a broad context to allow application to all xenobiotics and hence, to aid toxicological as well as pharmacological investigations. The trend away from descriptive models towards biologically based systems allowing mechanistic interpretation is stressed. In particular the development of kinetic approaches to characterise the formation and disposition of metabolites is described.

Absorption↗
PubMed1987

Kinetics of drug metabolism inhibition: use of metabolite concentration-time profiles.

A simple model simulating the kinetics of drug metabolism inhibition interaction is investigated. The relative sensitivity of drug and metabolite concentration-time profiles as indices of inhibition is assessed. Under steady-state conditions where inhibitor concentrations are maintained constant, the determination of metabolite in addition to drug kinetics provides little additional information when inhibition is nonselective in nature. However metabolite profiles do offer increased sensitivity when parallel routes of metabolism exist and there is selectivity of inhibitory action. Non-steady-state conditions are also investigated as they often apply in inhibition studies; the inhibitor is often administered as a single dose or as a multiple dosing regimen rather than by a constant rate intravenous infusion. Under the former conditions, when inhibitor concentrations in the body fluctuate during the study, metabolite kinetics can be more useful than drug kinetics. The changes evident in the metabolite concentration-time profiles are substantial due to both the inhibition per se and the nonlinearity in the system arising from inhibitor elimination. It is concluded that metabolite kinetics provide a useful aid in the detection of drug metabolism inhibition interactions.

Drug Interactions↗
PubMed1987

Theophylline and antipyrine disposition in smoking and non-smoking epileptic subjects.

Theophylline and antipyrine disposition has been compared in smoking epileptic patients, non-smoking epileptic patients and non-smoking healthy volunteers. Although clear differences in drug clearance and half-life were evident as a result of anticonvulsant drug therapy, no effect of smoking was discernible. Thus, additive effects from induction of the hepatic microsomal monooxygenase system in man by anticonvulsant drugs and polycyclic aromatic hydrocarbons (in cigarette smoke) were not evident.

Adult↗
PubMed1987

Dose-dependent pharmacokinetics of cimetidine in the rat.

The pharmacokinetics of cimetidine were studied in the rat after intraperitoneal administration of 10, 40 and 100 mg/kg. The area under the plasma concentration-time curve increased more than proportionately with dose. The total plasma clearance of cimetidine decreased as the dose increased (4.11 to 2.21 l/h per kg) with a consequent increase in half-life (24.0 to 37.9 min) but no change in volume of distribution (mean 2.31 l/kg). The fraction of dose excreted unchanged increased slightly with dose (0.37 to 0.45), whereas the fraction excreted as the sulphoxide metabolite decreased significantly with increased dose (0.35 to 0.14). Both the renal clearance (1.52 to 0.99 l/h per kg) and the formation clearance of the sulphoxide metabolite (1.45 to 0.30 l/h per kg) decreased with increasing dose. Residual clearance, calculated as the difference between total clearance and the sum of renal and metabolic clearance, did not change with dose (mean 1.08 l/h per kg). The formation clearance of the sulphoxide metabolite became saturated at a lower cimetidine concentration than the renal clearance.

Animals↗
PubMed1986

Temporal effects on antipyrine metabolite kinetics in Aroclor 1254-treated rats.

The in vivo consequences of a single dose of Aroclor 1254 (50 mg/kg) on the drug metabolizing capacity of rats were investigated. A noninvasive method, employing [N-methyl-14C]-antipyrine where both 14CO2 exhalation and urinary excretion of 4-hydroxy-, 3-hydroxymethyl-, and norantipyrine were monitored, was used. A group of rats were sequentially tested over a 3-week period to characterize temporal patterns. The antipyrine metabolite kinetic approach demonstrated that induction of hepatic cytochrome P-450 is maximal 3-6 days after Aroclor 1254 administration and the effects were apparent for at least a further 14-17 days. Evidence is presented to suggest selective effects of Aroclor 1254 on different cytochromes P-450 are apparent in vivo.

Animals↗
PubMed1986

Cervical spine movement during orotracheal intubation.

We measured cervical spine movement during orotracheal intubation in 16 anesthetized patients without neck injury. Comparisons were made using straight and curved laryngoscope blades without stabilization, Philadelphia collar stabilization, and in-line stabilization by an assistant. There was cervical spine movement in all cases. There was no significant difference in movement without stabilization when comparing straight and curved laryngoscope blades (P = .8536). There was no significant decrease in movement when a Philadelphia collar was applied (P = 1.000). There was a significant decrease in movement when in-line stabilization was applied (P = 0.0056). Although none of the methods tested totally prevented cervical spine movement during orotracheal intubation, the least movement was obtained by the use of in-line stabilization by an assistant. The type of laryngoscope blade used or application of a Philadelphia collar did not reduce movement significantly.

Adult↗
PubMed1986

Disposition of metronidazole and its effects on sulphasalazine metabolism in patients with inflammatory bowel disease.

The pharmacokinetics of metronidazole were studied after oral and intravenous administration to seven patients with Crohn's disease and five patients with ulcerative colitis. The oral/intravenous availability ratio was 0.97 +/- 0.2 in the Crohn's patients and 0.90 +/- 0.1 in the colitics (mean +/- s.e. mean). Plasma clearance was 3.24 +/- 0.2 l h-1 and 4.1 +/- 0.5 l h-1, respectively. These differences were not statistically significant. Ten of the patients on long term sulphasalazine were studied to observe the effect of 2 weeks metronidazole therapy on plasma sulphapyridine concentration. The sulphapyridine concentration changed from 22.1 +/- 2.0 micrograms ml-1 to 15.95 +/- 4.5 micrograms ml-1 in the Crohn's patients and 26.0 +/- 6.0 micrograms ml-1 to 36.4 +/- 8.5 micrograms ml-1 in the colitis group, pre- and post-metronidazole. These differences were not statistically significant. These results suggest that metronidazole does not interfere with diazo-link splitting of sulphasalazine and that patients with Crohn's disease handle metronidazole in a similar manner to patients with colitis.

Administration, Oral↗
PubMed1986

Effect of pregnenolone carbonitrile, promethazine and antipyrine pretreatment on antipyrine metabolite formation in rats.

The effect of three inducers of cytochrome P-450-mediated drug oxidations (Pregnenolone carbonitrile, promethazine and antipyrine) on antipyrine metabolite kinetics has been investigated using the urinary metabolite pattern and 14CO2 exhalation rate (CER)-time profile following [N-methyl-14C]antipyrine administration. The CER-time profiles showed the characteristic changes associated with induction, namely, increased maximum CER and decreased half-life, previously observed in phenobarbitone and beta-naphthaflavone-induced rats. Calculation of formation rate constants based on urinary recovery of 3-hydroxymethyl-, 4-hydroxy- and nor-antipyrine indicated no clear selectivity of induction by any pretreatment. However, the percentage increase of the latter two metabolites was two- to four-fold greater than for the former metabolite. The use of the metabolite ratio (3-hydroxymethylantipyrine/norantipyrine) is proposed to assess the qualitative nature of induction of antipyrine metabolism.

Animals↗
PubMed1985

Induction of cytochromes P-450 in pancreatic disease: consequence, coincidence or cause?

We have examined the pharmacokinetics of antipyrine and of theophylline--validated probes for cytochromes P-450 activities--in a series of patients with pancreatic disease. The half-life of each drug was significantly lower, and its clearance faster, in patients than in controls and this pattern was detected in the subgroups with acute pancreatitis (6), chronic pancreatitis (22), or pancreatic cancer (4). These data suggest induction of cytochromes P-450 in all forms of exocrine pancreatic disease. Enzyme induction is unlikely to be secondary to pancreatic malfunction since there was no correlation between prevailing exocrine status, as assessed by secretin-pancreozymin tests, and the half-life or clearance of either drug. The corollary is that induction of the mono-oxygenases by environmental agents, both recognised and unidentified, is a primary event in pancreatic disease. The possible relevance of this finding is discussed.

Adolescent↗
PubMed1985

Antipyrine metabolite kinetics in healthy human volunteers during multiple dosing of phenytoin and carbamazepine.

Antipyrine total clearance and the formation clearance of its major metabolites were studied in normal, healthy male volunteers before and after multiple dosing for approximately three weeks with phenytoin (six subjects) and carbamazepine (six subjects). Total antipyrine clearance increased on average by 91% after phenytoin dosing and by 61% after carbamazepine and individual increases correlated well with mean plasma concentrations of the anti-epileptic drug. The increase in total clearance resulted largely from increased formation clearances of the 4-hydroxy and 3-hydroxymethylantipyrine metabolites with minimal effect on the norantipyrine pathway, following treatment with both enzyme-inducing drugs. It is concluded that both phenytoin and carbamazepine have similar effects on antipyrine metabolism and that these effects are mediated by induction of specific forms of cytochrome P450.

Adult↗
PubMed1985

Changes in the disposition of promethazine during multiple dosing in the rabbit.

During a multiple dosing regimen, the area under the promethazine blood concentration-time profile progressively decreased indicating auto-induction of metabolism. The increase in promethazine clearance (mean 35%) was not reflected in changes in either elimination half-life or minimum blood concentrations during the dosing interval. This was attributed to a deep compartment in the disposition of promethazine in the rabbit. The changes in promethazine clearance were accompanied by proportionally larger changes in the clearance of the monodesmethylpromethazine metabolite. The effect of promethazine pretreatment on the clearance of antipyrine was also studied and was found to be significantly increased by a mean of 17% following pretreatment with promethazine. However, the changes in the clearance of antipyrine did not highly correlate with those of promethazine and monodesmethylpromethazine. This may indicate that promethazine induces metabolic systems in the rabbit for which antipyrine is not a good substrate.

Animals↗
PubMed1985

Effect of promethazine and isosafrole on rat-hepatic microsomal mono-oxygenase activity: comparison with classic inducers phenobarbitone and beta-naphthoflavone.

The characteristics of induction of rat-hepatic microsomal mono-oxygenase activity by promethazine and isosafrole have been investigated and compared with the classic inducers phenobarbitone and beta-naphthoflavone. Both promethazine and isosafrole pretreatments result in increased cytochromes P-450, and enhanced NADPH-cytochrome c reductase, aminopyrine N-demethylase, dichloronitroanisole O-demethylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase activity. Isosafrole but not promethazine increased the liver to body weight ratio. It is concluded that promethazine and isosafrole pretreatment produces an induction of the rat-hepatic microsomal mono-oxygenase system which shows both phenobarbitone- and polycyclic aromatic hydrocarbon-type characteristics.

Animals↗
PubMed1984

Drug metabolite concentration-time profiles: influence of route of drug administration.

In order to assess the contribution of an active metabolite to the overall pharmacological response following drug administration it is necessary to characterise the metabolite concentration-time profile. The influence of route of drug administration on metabolite kinetics has been investigated by computer simulation. Comparisons between simulated profiles and published concentration-time data have been carried out. A route dependence in metabolite concentration-time curves is readily apparent provided the metabolite kinetics are formation rate limited and the hepatic clearance of drug is greater than 25 l/h (medium to highly cleared). Oral drug administration produces a triphasic metabolite concentration-time profile whereas only two phases are discernable after intravenous drug administration. The magnitude of the difference in maximum metabolite concentration is directly proportional to the hepatic clearance of drug due to first-pass metabolite production. The route dependence in the shape of the metabolite concentration-time curves is most dramatic when the absorption and distribution of drug and the elimination of metabolite is rapid. A reduction in the rate of either of these processes alters the shape of the metabolite concentration-time profile such that the consequence of first-pass metabolite formation may be reduced.

Administration, Oral↗