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J B Houston

Publications and source records attributed to J B Houston.

At least 55 records · Page 3Linked to original sources
PubMed1995

Prediction of in vivo disposition from in vitro systems: clearance of phenytoin and tolbutamide using rat hepatic microsomal and hepatocyte data.

The kinetics of oxidation of phenytoin and tolbutamide were determined in freshly isolated hepatocytes and hepatic microsomes from male Sprague-Dawley rats. Similar enzyme kinetic models are applicable to the data from both in vitro systems; a two-site model for phenytoin with a high affinity (Km = 1-5 microM, based on unbound drug concentration), low capacity site and a low affinity, high capacity site, and a one-site model for tolbutamide. Steady-state infusion studies were performed to characterize the Michaelis-Menten parameters for phenytoin disposition in vivo, these data could also be described by a two-site metabolism model (Km 1.3 microM, intrinsic clearance 62 ml/min for unbound drug for the high affinity site). Comparison of in vivo and in vitro parameters (after scaling the latter parameters for either hepatocyte yield or microsomal recovery) showed excellent prediction of in vivo clearance of unbound drug from hepatocyte data (55 ml/min) but underprediction from microsomal data (17 ml/min). In contrast to phenytoin, the in vivo clearance of tolbutamide (1.5 ml/min for unbound drug) was equally well predicted by both hepatocyte (2.4 ml/min) and microsomal (3.1 ml/min) studies. The difference between the utility of in vitro systems to predict the in vivo clearance of these two drugs, which show similar pharmacrokinetic properties (low clearance restricted to unbound drug concentration in blood), may be a consequence of the particular terminal metabolite formed in each in vitro system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The six-day-old rat air pouch model of inflammation: characterization of the inflammatory response to carrageenan.

Inflammation was induced in the 6-day-old rat air pouch by injection of carrageenan. The model was characterized in terms of exudate volume, leucocyte influx, cell free protein, prostaglandin E2 levels, and granuloma formation. The time course of all these inflammatory markers, except prostaglandin E2, showed a 3-hr lag followed by a rapid increase to 8 hr. Thereafter, the rate of increase was much slower to 48 hr. Differential cell counts indicated a predominantly polymorphonuclear cell response (75%) during the first 48 hr. Prostaglandin E2 levels increased rapidly after a 3-hr lag, to a maximum of 440 +/- 140 ng/mL at 15 hr and thereafter quickly declined to 140 +/- 60 ng/mL at 21 hr. Prostaglandin E2 levels were the most sensitive inflammatory marker to (S+)-ibuprofen and were reduced dose dependently in the range 0.05 to 1 mg/kg. We have demonstrated the time course for duration of NSAID-induced reduction of prostaglandin E2 levels during inflammation in an individual animal. Rac-ibuprofen (0.1-1 mg/kg) reduced leucocyte influx at 3 and 5 hr, after which drug effects gradually diminished by 24 hr. Rac-ibuprofen at 1 mg/kg significantly reduced the volume of air pouch exudate recovered at 24 hr but had no effect on protein levels.

Animals↗
PubMed1994

Disposition of azole antifungal agents. III. Binding of fluconazole and other azoles in rat liver.

It has been shown for the azole antifungal agents, ketoconazole and DTP, that hepatic binding, is a major determinant of their volume of distribution and this observation is of particular interest in view of the well-documented avid binding of azoles to cytochromes P450. Whilst the hepatic binding characteristics of these two compounds are similar, their hepatic clearance differs markedly in terms of the rate of metabolism and the number and nature of metabolites produced. Fluconazole is a bis-triazole drug similar in structure to DTP but not subject to metabolism in rat. We have demonstrated by means of steady-state infusion studies the clearance of this azole (1.85ml/min/kg) to be independent of blood concentration over a 0.01-50mg/L range. Also fluconazole plasma protein binding is minimal (9.5%) and its blood:plasma ratio unity over a similar concentration range. Liver:blood partition coefficients for fluconazole are concentration dependent ranging from 30 to 2. The volume of distribution term is also nonlinear with concentration and can be correlated with the liver:blood partition coefficient. These findings are discussed together with earlier documented data on ketoconazole and DTP in terms of a tissue binding role for hepatic cytochromes P450. The similarity in behaviour of the hepatic partitioning of the three azoles contrasts markedly with the nature of (or lack of) hepatic metabolism.

Adrenal Glands↗
PubMed1994

Disposition of azole antifungal agents. II. Hepatic binding and clearance of dichlorophenyl-bis-triazolylpropanol (DTP) in the rat.

DTP (dichlorophenyl-bis-triazolylpropanol) was evaluated as a probe of drug-cytochromes P450 interactions in vitro and in vivo. Studies with rat liver microsomes demonstrate that DTP shows similar P450 binding affinity to its analog, ketoconazole, as determined by P450 difference spectra and inhibition of the metabolism of methoxycoumarin. As a more polar azole, DTP shows less affinity for rat plasma albumin (fraction unbound 0.56) than ketoconazole (fraction unbound 0.037). DTP metabolism is simpler than that of ketoconazole, with only one pathway, N-dealkylation which removes a triazole ring to yield DTP glycol. This primary metabolite is further metabolised to a carboxylic acid, a glycol glucuronide and a third unknown secondary metabolite (probably an acid glucuronide). Over a dose range of 0.1-24mg/kg there is complete mass balance recovery in urine via the five metabolites and unchanged drug. However DTP metabolism is dose dependent and while the affinity of DTP for the cytochromes P450 carrying out the initial dealkylation is high (1.5 microM based on unbound blood concentration), the capacity of the reaction is low (1 nmole/min). Under linear conditions, metabolic clearance is low (19ml/h), but ten-fold higher than renal clearance. The liver is the major distribution site for both DTP and ketoconazole. At low DTP concentrations, a specific high affinity process dominates the hepatic binding of DTP resulting in a liver:blood partition coefficient of approximately 30. Hepatic binding is concentration dependent and the progressive decrease in partition coefficient observed as the dose of DTP is escalated is coincident with a decrease in volume of distribution. The two saturable processes involved in the disposition of DTP result in an unusual concentration dependency in the blood concentration-time profile of this azole. Following administration of a high dose (10mg/kg) of DTP the log concentration-time profile is sigmoidal. At high concentrations (above 1mg/L) both the N-dealkylation and the hepatic binding of DTP are saturated, but as concentrations fall to approximately 0.05mg/L the former process becomes linear and the time profile is convex over this concentration range. At later times as DTP concentrations decline further, the tissue binding also reaches the linear region and the time profile becomes concave. Only at low concentrations (below 0.05mg/L) do both processes become first order and the true half life is evident.

Animals↗
PubMed1994

Relationship between enoxacin and ciprofloxacin plasma concentrations and theophylline disposition.

Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics. The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33-46) at steady state plasma concentrations of 0-33 mg.l-1, achieved by supplementing an intravenous bolus dose with a constant rate infusion. The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg.kg-1 were described using a competitive inhibition model. The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone. The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat. The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change. These values were 4.7 microM and 16.3 microM for ENOX and CIPRO, respectively. Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO. The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were 'designed out.'

Animals↗
PubMed1994

Experimental determination of a drug targeting index for S(+)ibuprofen using the rat air pouch model of inflammation.

We have used the rat air pouch model of inflammation and S(+)ibuprofen as an experimental model system to enable the quantitative assessment of the pharmacokinetic determinants of site specific drug delivery. S(+)ibuprofen (50 & 1mg/kg) was administered directly into six day old air pouches immediately following the injection of the irritant carrageenan. Serial exudate and plasma samples were collected and analysed for ibuprofen by HPLC. The procedure was repeated following administration of S(+)ibuprofen (20 & 5mg/kg) intravenously. The parameters describing events in the air pouch and plasma indicated linear kinetics over the doses employed. The dose normalised AUCs were then used to formulate a quantitative measure of benefit for S(+)ibuprofen delivered directly to the air pouch. A Drug Targeting Index (DTI) was calculated from the ratio of AUC in the air pouch and plasma following direct intrapouch administration divided by the same ratio following intravenous administration and gave a value of 130. This pharmacokinetic measure of benefit represents the maximum advantage afforded by the site specific delivery of S(+)ibuprofen as the whole of the administered dose is delivered directly to the site of action.

Animals↗
PubMed1993

Simultaneous assay of fluoroquinolones and theophylline in plasma by high-performance liquid chromatography.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of theophylline in plasma simultaneously with either ciprofloxacin, enoxacin or norfloxacin has been developed. It involves extraction of plasma with chloroform-isopropanol or dichloromethane-isopropanol prior to chromatography on a Spherisorb ODS2 column. The mobile phase is 15% acetonitrile in a phosphate buffer (pH 3.0) containing tetrabutylammonium hydrogen sulphate (4.4 mM) as an ion-pairing agent. Ultraviolet detection is carried out at 280 nm. Run time is less than 10 min for all three separations. The assays have been used to determine the effect of plasma concentrations of fluoroquinolone on theophylline clearance.

Animals↗
PubMed1993

Time-dependent disposition of beta-naphthoflavone in the rat.

The pharmacokinetics of beta-naphthoflavone (BNF) have been investigated in rats following various modes of intravenous administration. From intravenous bolus studies it was established that BNF showed a high blood clearance (130 ml/min/kg) and no detectable excretion of unchanged compound in the urine. The volume of distribution for BNF was large (6 L/kg), and binding to plasma proteins extensive (96%). Intravenous infusion studies where the length of infusion was increased from 1 to 8 hr showed marked signs of time-dependent pharmacokinetics. During continuous infusions the plasma concentrations accrued for approximately 1 hr, after which plasma concentrations declined in an apparent exponential fashion to a plateau value. In the short infusion studies the postinfusion half-life (27 min) was significantly shorter than the terminal half-life after bolus administration (40 min). Time-dependent clearance of BNF resulting from enhancement/induction of P450IA enzymes is proposed as the mechanism for these unusual pharmacokinetic features. The use of antipyrine as an independent probe for P450 activity gave similar trends in antipyrine clearance for various modes of BNF administration. Computer simulations based on an autoinduction model for time-dependent clearance were consistent with the observations on BNF in the rat.

Animals↗
PubMed1993

Disposition of azole antifungal agents. I. Nonlinearities in ketoconazole clearance and binding in rat liver.

The disposition of ketoconazole was characterized in the rat over a wide dose/concentration range. Bolus dose (0.03-10 mg/kg) studies indicate that plasma concentration-time profiles for ketoconazole are not superimposable when dose normalized because of nonlinearities occurring in both volume of distribution and clearance. The volume of distribution decreases from 3 to less than 1 L/kg, while the plasma clearance decreases 10-fold from 25 mL/min/kg as the dose is escalated. From these results, infusion rates were calculated to maintain the plasma concentrations achieved with particular bolus doses. The curvilinear relationship between steady-state plasma concentration (0.015-8.3 mg/L) and ketoconazole infusion rate (0.021-2.45 mg/hr/kg) was analyzed in terms of Michaelis-Menten kinetics. A Vmax of 3.2 mg/hr/kg and Km of 2.1 mg/L were obtained by nonlinear regression analysis. At the end of the ketoconazole infusion, liver, adrenals and kidneys were removed and assayed for ketoconazole. Tissue-to-plasma partition coefficients for the liver and adrenals showed a marked dependence upon steady-state plasma concentration. Both parameters (liver, 22; and adrenals, 53) showed a decrease of approximately 10-fold as the plasma concentrations were increased. In contrast, the kidney:plasma partition coefficient (1.8), blood:plasma concentration ratio (0.6), and plasma binding (96%) of ketoconazole did not show a concentration dependence over the range studied. It is concluded that the liver is an important determinant of ketoconazole's volume of distribution and that saturation of this process accounts largely for the reduction in volume of distribution with increasing dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Clinical prosthodontic management of a new implant system.

Just prior to the advent of the branemark implant, the Harvard consensus on implantology condemned all maxillary implants. While implant utilization has skyrocketed in the last few years integration of implants in the maxilla is a persistent problem and even the branemark implant enjoys a lower success rate in this bone. These observations underscore the higher failure rate of the maxillary implant and suggest the need for development of a new implant design configuration that would favour long term successful integration despite the attenuated maxillary attributes. Such is the intent of the ostial implant. The basic considerations concerning this device, its bioengineering, experimental performance and clinical trials are discussed elsewhere. The purpose of this paper is to describe clinical prosthodontic applications of this implant system.

Dental Implants↗
PubMed1992

Use of the rat air pouch model of inflammation to evaluate regional drug delivery.

We have used the rat inflammatory air pouch model to investigate some of the pharmacokinetic and pharmacodynamic issues relating to regional drug delivery. S(+)Ibuprofen was administered either intravenously or directly into the air pouch at the same time as the irritant (carrageenan). Serial samples of exudate and plasma were then taken and assayed for drug concentrations and various efficacy markers. Ibuprofen given intrapouch, was found to inhibit in a dose-dependent manner the concentration of prostaglandin E2 and the number of white cells in the exudate. Plasma and pouch concentration-time profiles are described for s(+)Ibuprofen: there is evidence for greater drug retention in the pouch than in plasma following regional and systemic delivery.

Animals↗
PubMed1991

Nonlinear first-pass metabolism of nifedipine in healthy subjects.

1. A dose-range study was carried out with nifedipine (NF) in 11 healthy subjects, who received orally 5, 10 and 20 mg in capsules (cap) and 20 mg as slow-release tablet. 2. The dose-normalized area under the curve (AUC) of NF showed significant nonlinearity: AUC of 5 mg (cap) was 312 +/- 179, of 10 mg (cap) 357 +/- 186 and of 20 mg (cap) 424 +/- 174 (ng.h/ml). The AUC of the tablet was significantly lower than that of 10 and 20 mg (cap), but not different from 5 mg (cap). 3. The dose-normalized AUC of the pyridine metabolite (M-0) significantly decreased with increasing dose: AUC of 5 mg (cap) was 244 +/- 88, of 10 mg (cap) 194 +/- 96 and of 20 mg (cap) 120 +/- 37 (ng.h/ml). 4. The excretion of M-I (which is ester-hydrolysed M-0) into urine was not different for any of the doses. 5. It is concluded that NF exhibits nonlinear first-pass metabolism, which concomitantly affects the formation of M-0, but not that of M-I.

Female↗
PubMed1990

Drug metabolizing capacity in vitro and in vivo--I. Correlations between hepatic microsomal monooxygenase markers in beta-naphthoflavone-induced rats.

Relationships between and within in vivo and in vitro markers of drug oxidative metabolism have been investigated in rats displaying a wide range of hepatic microsomal monooxygenase activity due to prior treatment with various doses of the inducing agent beta-naphthoflavone (BNF). BNF induction produced large dose-related changes in the in vivo clearance (CL) of theophylline (TH), antipyrine (AP) and the individual AP metabolite formation clearances, 4-hydroxyantipyrine (4H) and norantipyrine, and the in vitro parameters, 7-ethoxycoumarin O-deethylase, 7-ethoxyresorufin and P450. No trends were observed with the formation clearance of 3-hydroxymethylantipyrine and 7-methoxycoumarin O-demethylase whilst a negative response was observed with aldrin epoxidase. The selectivity of the markers towards BNF induction was coincident with the degree of covariance observed between these parameters. Strong correlations were observed in particular between CL(TH) and CL(4H) and ECOD and EROD indicating the high predictive value of these parameters. These studies demonstrate that under the well controlled conditions which may be imposed in animal environments predictively useful relationships (r2 greater than 0.8) can be established between in vitro and in vivo markers of hepatic microsomal monooxygenase activity.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

Drug metabolizing capacity in vitro and in vivo--II. Correlations between hepatic microsomal monooxygenase markers in phenobarbital-induced rats.

Pretreatment with various doses of phenobarbital (PB) has been used to create a pool of rats with a wide range of hepatic microsomal monooxygenase activity to systematically examine relationships between and within in vivo and in vitro markers. The in vivo clearance of tolbutamide (TOL), theophylline (TH), antipyrine (AP) and its metabolites were determined in the same rats used for hepatic microsome preparation and assessment of P450 content and activities (via 7-ethoxycoumarin O-deethylase (ECOD), 7 ethoxyresorufin O-deethylase, 7-methoxycoumarin O-demethylase (MCOD) and aldrin epoxidase determinations). A graded dose-response relationship was found between PB treatment and most but not all parameters. The need for careful selection of in vivo and as well as in vitro markers is apparent from these studies. The most responsive parameters--TOL and AP clearances, MCOD and ECOD activities--were also those producing the strongest in vivo-in vitro correlations. Despite the diffuse nature of the PB induced response in P450 complement, good predictive relationships were apparent between ECOD and TOL clearance (r2 = 0.88).

7-Alkoxycoumarin O-Dealkylase↗
PubMed1989

Factors contributing to the accelerated clearance of theophylline and antipyrine in adults with exocrine pancreatic disease.

1. Oxidative drug metabolizing capacity has been assessed by oral antipyrine and/or theophylline tests in consecutive patients with chronic pancreatitis (CP; alcoholic 24, idiopathic 47), acute pancreatitis (AP; 28) and pancreatic cancer (CA; 11). Most of the patients had drastically reduced their alcohol consumption and dietary fat intake for variable periods before the tests. Excellent bioavailability of theophylline was confirmed from paired oral and intravenous tests in seven subjects, including two with exocrine pancreatic failure. 2. The clearance of theophylline in the patients was faster than in 15 controls with a 'healthy lifestyle' [median 104 (range 18-320) ml h-1 kg-1 vs median 68 (range 50-97) ml h-1 kg-1, P less than 0.01]. The difference was especially apparent in the groups with alcoholic CP (P less than 0.001 and idiopathic CP (P less than 0.01), but not in the AP and CA group as a whole, although drug clearance in some 50% of those cases exceeded the reference range. 3. There was good correlation between theophylline and antipyrine clearance in a subset of 91 subjects who had both tests (15 controls, 76 patients), but antipyrine was much less sensitive as a marker of enzyme induction. This suggests that enzyme induction in pancreatic disease preferentially involves the polycyclic aromatic hydrocarbon-inducible subfamily of cytochrome P-450. 4. The lack of correlation between pancreatic secretory capacity in 56 cases, judged by a secretin-pancreozymin test, and theophylline clearance suggests that enzyme induction is not secondary to pancreatic dysfunction. 5. Multivariate regression analysis identified approximately 50% of variability in clearance of each probe.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗