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Biomedical subjects

K A Bachmann

Publications and source records attributed to K A Bachmann.

At least 19 recordsLinked to original sources
PubMed1995

The influence of anesthetic agents on rat hepatic cytochromes P450 in vivo.

The objective of this study was to identify which anesthetics when used acutely will affect cytochrome P450 (CYP) activity in male Sprague-Dawley rats in vivo. The anesthetics tested were fentanyl citrate, alpha-chloralose, ketamine, urethane (ethyl carbamate), halothane, and ether. CO2 anesthesia was used as the control comparator. Theophylline was used as a probe for CYP1A activity, phenobarbital for CYP2B/2C, flecainide for CYP2D1, and ethosuximide for CYP3A activity. All probes were administered via tail vein injection after anesthetic-induced loss of the righting reflex. Single sample probe clearances were estimated, and used as an index of CYP activity. Fentanyl citrate, alpha-chloralose, halothane, and ether did not have statistically significant effects on any of the CYP activities. Ketamine did not significantly affect CYP1 or CYP2B/2C activity. However, it decreased the clearance of flecainide (i.e. CYP2D1 activity) by 13.4% (p < 0.001) and the clearance of ethosuximide (i.e. CYP3A activity) by 17.6% (p < 0.0001). Urethane increased the clearance of theophylline by 91.5% (p < 0.0001), and decreased the clearance of ethosuximide by 40.5% (p < 0.0001) though it did not affect CYP2B/2C or CYP2D1 activities significantly. From this data, we conclude that a single dose of ketamine mildly inhibits the activity of CYP2D1 and CYP3A, and a single dose of urethane strongly inhibits CYP3A but increases CYP1A activity.

Analysis of Variance↗
PubMed1994

Short report: a comparative study of the interaction between antacid and H2-receptor antagonists.

The influence of concomitant antacid administration on the relative bioavailability of the H2-receptor antagonists cimetidine, famotidine, nizatidine and ranitidine, was investigated in a panel of 21 healthy, adult male volunteers in an eight-way crossover trial. Administration with antacid reduced the bioavailability of all agents tested. The reduction in area under the serum concentration-time curve (AUC) was greatest for cimetidine (23%) and ranitidine (26%) and least for nizatidine (12%) and famotidine (19%). Reductions in peak serum concentration (Cmax) followed a similar pattern. The times of peak serum concentrations were not affected by antacid. Comparison of the relative bioavailability among all drugs tested showed no statistically significant differences in the effect of antacid administration on these agents. However, a high degree of intersubject variability was observed.

Adult↗
PubMed1994

Drug interactions of H2-receptor antagonists.

Three drug interactions of nizatidine and of other antisecretory agents were studied comparatively. First, the effects of nizatidine, cimetidine and ranitidine on the dispositional kinetics of theophylline were evaluated in chronic obstructive pulmonary disease (COPD) patients. Second, the effect of magnesium/aluminium hydroxide on the relative bioavailability of nizatidine, famotidine, cimetidine and ranitidine was evaluated in healthy volunteers. Finally, the effects of nizatidine and omeprazole on the dispositional kinetics of phenytoin were evaluated in healthy volunteers. Only cimetidine altered the steady-state kinetics of oral theophylline, slowing theophylline clearance by 25%. Each of the H2-receptor antagonists exhibited a modest decline in relative bioavailability when ingested with antacid. Antacid ingestion decreased the bioavailability of famotidine, ranitidine and cimetidine by 20-25%, and the bioavailability of nizatidine by 12%. Each of these effects was statistically significant. Finally, it was found that neither omeprazole nor nizatidine affected the single dose kinetics of phenytoin.

Adolescent↗
PubMed1994

Exercise training does not alter cytochrome P-450 content and microsomal metabolism.

The purpose of this investigation was to determine whether increased endurance exercise capacity alters total hepatic cytochrome P-450 content and cytochrome P-450 (CYP1A and CYP2B) mediated hepatic microsomal mixed-function oxidase drug metabolism. Twenty adult male Sprague-Dawley rats were randomly assigned to either a control (C) or an endurance trained group (ET). ET rats were progressively trained 5 d.wk-1 for 11 wk. Both C and ET rats were administered in random order single posttraining doses of probe drugs theophylline (probe for CYP1A) and antipyrine (probe for CYP2B). Soleus muscle citrate synthase activity of ET rats was significantly greater (P < 0.01) than for C rats (mean +/- SD; C, 26.4 +/- 1.3 mumol.g-1.min-1; ET, 46.1 +/- 2.7). In contrast, total liver cytochrome P-450 content was not significantly different (P > 0.01) among C and ET rats (mean +/- SD; C, 0.554 +/- 0.055 nmol.mg-1 liver protein; ET, 0.604 +/- 0.080). Likewise, the posttraining C and ET single-sample plasma clearances of theophylline (mean +/- SD; C, 1.89 +/- 0.360 1.h-1.kg-1 total liver weight; ET, 2.08 +/- 0.49) and antipyrine (mean +/- SD; C, 6.44 +/- 1.56 1.h-1.kg-1 total liver weight; ET, 6.51 +/- 1.02) were not significantly different (P > 0.01). Therefore, it was concluded that strenuous endurance training of 11 wk duration did not alter total hepatic cytochrome P-450 content or CYP1A or CYP2B activity.

Animals↗
PubMed1992

The effects of cobalt chloride, SKF-525A, and N-(3,5-dichlorophenyl)succinimide on in vivo hepatic mixed function oxidase activity as determined by single-sample plasma clearances.

1. Four drugs--antipyrine, theophylline, quinidine, and ethosuximide--were used as probes of in vivo hepatic mixed function oxidase (MFO) activity. Functional MFO activity was evaluated by estimating probe clearances subsequent to pretreatment of rats with either cobalt chloride, SKF-525A, or N-(3,5-dichlorophenyl) succiminide (NDPS). 2. Clearances of each probe were estimated from single plasma concentration measurements. Each pretreatment altered the clearances of this panel of probes in a different way. NDPS pretreatment increased theophylline clearance while slowing quinidine and ethosuximide clearances. SKF-525A slowed all probe clearances except for ethosuximide. Cobalt chloride slowed all probe clearances except for theophylline. 3. The use of multiple probes as substrates for the hepatic cytochrome P-450 system can provide some insight into the functional consequences of xenobiotic exposures on that system. Moreover, xenobiotic-induced functional changes on hepatic MFO when assessed in vivo appear to be modest relative to changes in in vitro activity or hepatic cytochrome P-450 content. This minimally invasive multiprobe method may be useful for assessing xenobiotic influences on human hepatic MFO in vivo.

Animals↗
PubMed1991

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of phenobarbitone on human hepatic drug metabolism.

1. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Clearance estimates were calculated in healthy young adult male volunteers either taking no pretreatment, or taking phenobarbitone (PB) 100 mg nightly for 3 nights. This intermittent regimen (3 nights on, followed by 4 nights off) was repeated for at least 3 consecutive weeks prior to challenge with an individual probe. 2. Valproic acid was selected as a probe of both peroxisomal and microsomal beta-oxidase activity; antipyrine, phenytoin, quinidine, and carbamazepine were selected as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyl transferase activity. 3. Clearances of all probes except lorazepam, theophylline and phenytoin were approximately 20-30% faster in PB-treated than in control subjects; however, only in the case of carbamazepine did the increased clearance approach statistical significance. Neither phenytoin nor theophylline clearances were increased by PB. 4. A clearance index (probe CL for PB-treated subjects divided by probe CL for untreated subjects) was calculated for each probe, and an ordinal transformation of the log of the resultant ratio was plotted for each probe giving rise to a 'handprint' of the effect of PB on drug-metabolizing activity.

Adolescent↗
PubMed1990

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.

Antipyrine↗
PubMed1989

Accuracy of two equations in determining normalized phenytoin concentrations.

The accuracy of two equations in normalizing total phenytoin concentrations in the presence of renal failure or hypoalbuminemia was evaluated in 11 renal failure and 23 hypoalbuminemic patients. Blood samples were obtained from hospitalized patients receiving phenytoin and were assayed for free and total phenytoin concentrations. Estimated normalized phenytoin concentrations based on free drug concentration were compared statistically with normalized concentrations calculated from the two equations via Student's t-test. The equation for normalizing phenytoin concentrations in hypoalbuminemic patients significantly underpredicted normalized phenytoin concentrations 15.7 +/- 8.5 versus 19.9 +/- 12.1 mg/L (p less than 0.001). In patients with renal failure, the mean phenytoin concentration from the respective equations and that based on free concentration were 14.1 +/- 6.2 and 14.0 +/- 7.9 mg/L, respectively. However, in 5 of 11 renal failure patients the equation resulted in over- or underprediction by at least 25 percent. Neither equation should be used clinically to normalize phenytoin concentrations in these patient populations.

Adult↗
PubMed1989

The suitability of carbamazepine as a single-sample probe of human mixed function oxidase activity.

1. Carbamazepine concentrations measured in plasma and plasma ultrafiltrates by fluorescence polarization immunoassay (f.p.i.a.) from 0 to 48 h post-dose were used to calculate CL, V, clearance of plasma unbound drug (CLunb), Vunb; mean (+/- SD) values for these were: 0.017 l/kg/h (+/- 0.004), 1.05 l/kg (+/- 0.14), 0.058 l/h/kg (+/- 0.012), and 4.28 l/kg (+/- 0.41), respectively. 2. A single-dose, single-sample procedure for estimating carbamazepine oral clearance was evaluated with a view to using carbamazepine as a probe in screening for host factor influences on human drug metabolism. Single sample estimates of carbamazepine clearance (CL) were closest to multiple sample values for carbamazepine clearance (CL) when blood samples were collected 48 h after carbamazepine ingestion. This was the case for plasma total carbamazepine and plasma unbound carbamazepine. 3. A value of 1.1 l/kg was used for V in calculating all single sample estimates of clearance (CL), and a value of 4.3 l/kg was used to calculate single sample estimates of clearance of plasma unbound drug (CLunb). The mean prediction error (MPE) was negatively biased for CL and CLunb values calculated from single carbamazepine concentrations in samples collected at 24, 36, and 48 h post-dose. MPE was less than 5% errant for CL and less than 1% errant for CLunb when those parameters were calculated from 48 h concentrations of plasma total carbamazepine or plasma unbound carbamazepine, respectively. Root mean squared error (r.m.s.e.) was lost lowest when 48 h post-dose samples were used for single-sample clearance estimates.

Administration, Oral↗
PubMed1989

The use of single-sample clearance estimates to probe hepatic drug metabolism in rats. IV. A model for possible application to phenotyping xenobiotic influences on human drug metabolism.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multi-sample estimates of clearance for carbamazepine, quinidine, and paracetamol. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates (CL) corresponded closely to multi-sample clearance estimates. Best post-dose sampling times were: carbamazepine, 3 h; quinidine, 10 h; and paracetamol, 6 h. 2. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of hepatic drug-metabolizing activity in rats. Valproic acid was investigated as a probe of microsomal and peroxisomal oxidases; antipyrine, theophylline, ethosuximide, carbamazepine and quinidine as probes of hepatic mixed-function oxidases (MFO), and paracetamol as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely, probe CL after xenobiotic pretreatment divided by control probe CL) was calculated for each probe. Eight pretreatments were used: phenobarbital (PB), beta-naphthoflavone (beta NF), polychlorinated biphenyls (PCB), rifampin, pregnenolone-16 alpha-carbonitrile (PCN), clofibric acid, cimetidine, and piperonyl butoxide. The effect of each xenobiotic pretreatment on all probe CL values was consolidated and plotted as the logarithm of the CI, and a distinct pattern or handprint evolved for each pretreatment. 4. We conclude that the use of multiple single-sample probes of hepatic MFO activity can be useful in structuring handprints to characterize xenobiotic-mediated effects on hepatic MFO. This minimally invasive in vivo approach may have application in investigating and possibly phenotyping MFO activity in human subpopulations that are subject to sustained exposure to particular xenobiotics.

Animals↗
PubMed1988

Predicting the ciprofloxacin-theophylline interaction from single plasma theophylline measurements.

The effect of ciprofloxacin treatment on theophylline clearance was evaluated with a theophylline multiple dose, multiple sample protocol and with a single dose, single sample protocol. The object was to determine whether a single dose, single sample protocol for estimating theophylline clearance could be used as a screening strategy for evaluating host factor influences on theophylline clearance. Ciprofloxacin (750 mg per os) was administered every 12 h for nine doses in the multidose study and every 12 h for seven doses in the single dose protocol. Subjects were sixteen healthy, non-smoking young adult males. The oral clearance of theophylline at steady state, (CL/F)ss, decreased from a mean (+/- s.d.) value of 0.035 (+/- 0.008) 1 h-1 kg-1 to 0.024 (+/- 0.004) 1 h-1 kg-1 during ciprofloxacin treatment. Single sample estimates of theophylline clearance, CL/F, similarly decreased from 0.040 (+/- 0.014) 1 h-1 kg-1 to 0.018 (+/- 0.008) 1 h-1 kg-1. Mean theophylline clearances were significantly different when comparing control with ciprofloxacin treatment means (P less than 0.01), but were not different when comparing single sample vs multiple sample clearances for a given treatment (i.e. control or ciprofloxacin). It is concluded that a single dose, single sample strategy may be used in screening for host-factor influences on theophylline clearance.

Administration, Oral↗
PubMed1988

Multiple-dose pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to infected, seriously ill, elderly patients.

The pharmacokinetics of cefoperazone and sulbactam in combination were evaluated in six, elderly, seriously ill patients treated with the drug combination for intra-abdominal infections. After giving informed consent, three males and three females aged 63.5 to 77.5 (mean 67.9) years and weighing 54.5 to 86.8 (mean, 67.6) kg were treated with cefoperazone (2.0 g) and sulbactam (1.0 g) infused intravenously every 12 h for at least 5 days. Cefoperazone and sulbactam pharmacokinetics were characterized on both days 1 and 5 of treatment. Eleven serial blood samples were obtained just prior to and following dose 1 on days 1 and 5 of treatment. Mean estimates of cefoperazone maximal concentration in plasma (Cmax), area under the curve of drug concentration in plasma versus time (AUC), half-life (t 1/2), apparent volume of distribution by the area method (Varea), apparent volume of distribution at steady state (Vss), and total body clearance (CL) for day 1 (day 5) were 297.5 237.5) micrograms/ml, 1,247 (1,063) micrograms.h/ml, 7.0 (4.9) h, 16.1 (13.4) liter, 13.1 (14.4) liter, and 28.9 (34.2) ml/min, respectively. Day 1 (day 5) mean values for sulbactam Cmax, AUC, t 1/2, Varea, Vss, and CL were 110.3 (78.0) micrograms/ml, 228 (217) micrograms.h/ml, 3.4 (2.5) h, 26.1 (18.5) liter, 18.9 (15.4) liter, and 97 (94) ml/min, respectively. Both drugs evidenced slower elimination and greater pharmacokinetic variability in these patients compared with values previously reported for normal volunteers. As patients improved during the course of therapy, the only pharmacokinetic parameter significantly changed between days 1 and 5 was a shortened sulbactam t 1/2. Our inability to find substantial evidence of pharmacokinetic normalization may have been related to sample size and study duration. Both drugs were present in potentially therapeutic concentrations for the entire 12-h dosing interval, but without undue accumulation from days 1 to 5.

Abdomen↗
PubMed1988

The use of single sample clearance estimates to probe hepatic drug metabolism in rats. I.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multisample estimates of clearance. When plasma concentrations were measured at various post-dose times, both individual and mean values of single sample clearance estimates, Cl, corresponded closely to multisample clearance estimates, Cl, and significant differences between Cl and Cl could not be detected. 2. Best post-dose sampling times were: theophylline, 6 h; phenytoin, 2 h; valproic acid, 20 min; antipyrine, 4 h; and S-warfarin, 48 h. 3. When theophylline clearance was evaluated by both multisample and single sample experiments during diethyl ether versus urethane anaesthesia, clearances were about 50% slower for ether-anaesthetized rats. This outcome was qualitatively and quantitatively the same regardless of whether single sample or multiple sample clearances were estimated, and single sample theophylline clearances were virtually identical to multisample clearances under both anaesthetic conditions. 4. We conclude that multiple drugs can be potentially useful for probing hepatic drug metabolizing activity in rats when using a single plasma measurement to estimate clearance. An appropriate array of such probes might effectively be used to handprint host-factor influences on drug metabolizing activity.

Animals↗
PubMed1988

The use of single sample clearance estimates to probe hepatic drug metabolism in rats. II.

1. Single sample clearance estimates, Cl, were calculated for each of five drugs employed as probes of hepatic drug-metabolizing activity in rats. Probe drugs were theophylline, phenytoin, valproic acid, antipyrine, and S-warfarin. Cl values were calculated for each probe in animals pretreated with phenobarbital, isosafrole, beta-naphthoflavone, or clofibrate. Control animals were pretreated with vehicle only. 2. A clearance index (c.i., probe Cl after pretreatment divided by probe Cl control) was calculated for each probe and each pretreatment regimen, and data were consolidated to give different probe-based handprints of the pretreatment effects. 3. S-Warfarin was the least specific probe as its c.i. was greater than 1.0 subsequent to each pretreatment. Theophylline appeared to be the most selective probe since its c.i. deviated significantly from unity (3.56) only after beta-naphthoflavone pretreatment. Phenytoin exhibited c.i. values less than unity after each pretreatment indicating that it may not, when used as a single sample probe of hepatic drug-metabolizing activity, effectively discriminate between inductive or inhibitory effects of xenobiotics. 4. Multi-probe-based handprints of hepatic drug-metabolizing activity structured from simple single sample estimates of probe clearance have potential in the rapid screening of xenobiotic-induced alterations of drug-metabolizing enzyme activity.

Animals↗
PubMed1987

Use of three probes to assess the influence of sex on hepatic drug metabolism.

Clearances of phenytoin (PHT), ethosuximide, and theophylline were estimated by a single-dose, single-sample strategy in healthy, young adult men and women. PHT concentrations were measured in salivary ultrafiltrates, ethosuximide concentrations were measured in saliva, and theophylline concentrations were measured in plasma. Estimates of the clearances of these three probes of hepatic drug-metabolizing enzymes revealed a trend toward slightly lower clearances among women compared to men: mean PHT clearance 15% lower, ethosuximide clearance 27% lower, and theophylline clearance 14% lower. However, only differences in ethosuximide clearances were statistically significant. The use of oral contraceptive steroid (OCS) drugs on PHT and ethosuximide clearance was examined, and no significant effects were detected.

Adult↗
PubMed1986

Inability of ibuprofen to alter single dose phenytoin disposition.

The effect of ibuprofen treatment (1600 mg day-1 per os for 7 days) on single dose (300 mg per os) dispositional parameters of phenytoin (DPH) was evaluated in 10 healthy males. Ibuprofen slightly increased the free fraction of DPH from mean (+/- s.d.) value of 6.9 (+/- 0.7)% to 7.8 (+/- 0.3)% (P less than 0.01). DPH total clearance (CL/F) was not significantly changed going from a value of 0.027 (+/- 0.009) 1 h-1 kg-1 to 0.032 (+/- 0.014) 1 h-1 kg-1 (0.05 less than P less than 0.1). Intrinsic unbound DPH clearance (CLuint/F) was unaffected by ibuprofen treatment. Neither DPH's apparent volume of distribution (V/F) nor the apparent volume of distribution of unbound DPH (Vunb/F) were significantly altered by ibuprofen treatment. The slight changes in DPH plasma protein binding that are due to concurrent ibuprofen treatment in doses of 1600 mg day-1 are not likely to produce important changes in DPH dispositional parameters.

Adult↗