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PubMed1997

Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat.

Neuropathic pain remains a significant clinical problem. Current understanding implicates the spinal cord dorsal horn N-methyl-d-aspartate (NMDA) receptor apparatus in its pathogenesis. Previous reports have described NMDA antagonist reduction of nerve injury-induced thermal hyperalgesia and formalin injection-related electrical activity. We examined a panel of spinally administered NMDA antagonists in two models: allodynia evoked by tight ligation of the fifth and sixth lumbar spinal nerves (a model of chronic nerve injury pain), and the formalin paw test (a model wherein pretreatment with drug may preempt the development of a pain state). A wide range of efficacies was observed. In the nerve injury model, order of efficacy (expressed as percent of maximum possible effect +/- S.E.), at the maximum dose not yielding motor impairment, was memantine (96 +/- 5%) = AP5 (91 +/- 7%) > dextrorphan (64 +/- 11%) = dextromethorphan (65 +/- 22%) > MK801 (34 +/- 8%) > ketamine (18 +/- 6%). For the formalin test, the order of efficacy was AP5 (86 +/- 9%) > memantine (74 +/- 5%) > or = MK801 (67 +/- 16%) > dextrorphan (47 +/- 16%) > dextromethorphan (31 +/- 12%) > ketamine (17 +/- 15%). In the nerve injury model, no supraspinal action was seen after intracerebroventricular injections of dextromethorphan and ketamine. NMDA antagonists by the spinal route appear to be useful therapeutic agents for chemically induced facilitated pain as well as nerve injury induced tactile allodynia. It is not known what accounts for the wide range of efficacies.

2-Amino-5-phosphonovalerate↗

PubMed1997

CYP2D6-related oxidation polymorphism in a Canadian Inuit population.

The xenobiotic oxidation polymorphism associated with cytochrome P450 2D6 (CYP2D6) was investigated in 152 genetically related and unrelated healthy Inuit subjects living in the High Arctic of eastern Canada. Phenotyping was based on HPLC determination of the CYP2D6-related dextromethorphan metabolic ratio in overnight urine samples after oral administration of 30 mg dextromethorphan hydrobromide. The log metabolic ratio was bimodally distributed, with three subjects classified as poor metabolizers (PMs). In subjects unrelated in the first degree, the incidence of the PM phenotype was 3 of 90 or 3.3%. PCR-based analyses of DNA for variants of the CYP2D6 gene demonstrated that the PMs of dextromethorphan had the defective allele CYP2D6*4. The estimated frequency of the CYP2D6*4 allele was 0.067-0.083, which is lower than the frequency in Caucasians but higher than the frequency in Oriental populations. The CYP2D6*3 and the CYP2D6*6 alleles were not detected in the Inuit population. The CYP2D6*10 allele was present in only four unrelated subjects, classified as extensive metabolizers (EMs), resulting in an estimated allele frequency of 0.022, which is much lower than in Oriental populations. This study demonstrated the existence of the CYP2D6 polymorphism in Canadian Inuit, while the frequencies of allelic variants of CYP2D6 point to the uniqueness of this population. Several important therapeutic drugs that are being prescribed in Arctic communities will have altered pharmacokinetics in PMs of CYP2D6.

Adolescent↗

PubMedDate not supplied

Effect of protein-calorie malnutrition on cytochromes P450 and glutathione S-transferase.

Protein-calorie malnutrition (PCM) can develop both from inadequate food intake and as a consequence of diseases such as cancer and AIDS. Several studies have shown that PCM can alter drug clearance but little information is available on the effect of PCM on individual cytochrome P450 isoforms and phase II conjugation enzymes. The aim of the present study was to begin a systematic evaluation of the effect of PCM on the activity of individual drug metabolizing enzymes in a rat model of PCM. Control and PCM rats received isocaloric diets which contained either 21% or 5% (deficient) protein. After 3 weeks, the animals were sacrificed and microsomal and cytosolic fractions prepared. Ethoxyresorufin O-deethylation (EROD), chlorzoxazone 6-hydroxylation, dextromethorphan N- and O-demethylation and 1-chloro-2,4-dinitrobenzene (CDNB) conjugation were used as measures of CYP1A, CYP2E1, CYP3A2, CYP2D1 and glutathione S-transferase (GST) activity, respectively. Additionally, NADPH-cytochrome P450 reductase activity was measured in the liver microsomes. PCM significantly reduced the maximum velocity (Vmax) of all model reactions studied. However, differential effects were observed with respect to K(m) values of the reactions. The K(m) values for EROD and dextromethorphan N-demethylation were significantly increased in PCM animals, whereas the K(m) values for chlorzoxazone 6-hydroxylation and dextromethorphan O-demethylation were decreased. In contrast, the K(m) value for CDNB conjugation was unchanged. When NADPH-cytochrome P450 reductase activity was compared, a 29% reduction in reductase activity was noted in PCM animals as compared to controls. Thus, it appears that PCM decreases the overall activity of certain phase I and phase II metabolism enzymes in rat liver while exhibiting differential effects on K(m). Furthermore, this reduction in activity may be due in part to diminished activity of cytochrome P450 reductase.

Animals↗

PubMed1991

Effects of sigma ligands on mouse cerebellar cyclic guanosine monophosphate (cGMP) levels in vivo: further evidence for a functional modulation of N-methyl-D-aspartate (NMDA) receptor complex-mediated events by sigma ligands.

In the present investigation, the effects of sigma ligands [WY-47384 [8-fluoro-2,3,4,5-tetrahydro-2[3-(3-pyridinyl)propyl)1H- pyrido(4,3b)indole], (+)-pentazocine, (+)-SFK 10,047 (N-allylnormetazocine), mafoprazine, opipramol, dextromethorphan, dextrorphan, (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine], (-)-butaclamol, DTG [1,3-di(2-tolyl)guanidine], rimcazole, ifenprodil and BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoropyrimidinyl)-1-piperazine butanol]] on harmaline-, pentylenetetrazol (PTZ)-, methamphetamine (MA)- and D-serine-induced increases in mouse cerebellar levels of cGMP were determined. Ifenprodil, BMY-14802, dextromethorphan, dextrorphan, (+)-SKF 10,047, opipramol and mafoprazine reversed harmaline-, PTZ-, MA- and D-serine-induced increases in levels of cGMP. Rimcazole reversed only the harmaline-induced response. WY-47384 reversed harmaline-, MA-, D-serine-, but not PTZ- or quisqualate-induced increases in levels of cGMP. (+)-Pentazocine attenuated harmaline- and D-serine-, but not PTZ- and MA-induced cGMP responses. Haloperidol did not affect harmaline- and D-serine-induced cGMP responses. (+)-3-PPP and (-)-butaclamol did not affect any of the responses studied. Furthermore, (+)-3-PPP-induced increases in levels of cGMP were reversed by the competitive N-methyl-D-aspartate (NMDA) antagonist, CPP]3-(2-carboxypiperazin-4-yl)propyl- 1-phosphonic acid, the non-competitive NMDA antagonist, (+)-MK-801 (dizocilipine maleate), the NMDA-associated glycine receptor antagonist, HA-966 (3-amino-1-hydroxypyrrolidin-2-one), the partial glycine agonist, DCS (D-cycloserine) as well as by the sigma ligands, ifenprodil, WY-47384, (+)-pentazocine, (+)-SKF 10,047, dextromethorphan and dextrorphan but not by rimcazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Activities of cytochrome P450 1A2, N-acetyltransferase 2, xanthine oxidase, and cytochrome P450 2D6 are unaltered in children with cystic fibrosis.

The activities of hepatic cytochrome P450 (CYP) 1A2, N-acetyltransferase 2 (NAT-2), xanthine oxidase (XO), and CYP2D6 were evaluated in 12 young children (aged 3-8 years) with mild cystic fibrosis (CF) and 12 age-matched healthy control subjects by use of standard caffeine and dextromethorphan phenotyping methods. Subjects were given 4 oz of Coca-Cola (approximately 35 mg caffeine) (The Coca-Cola Company, Atlanta, Ga) and a single 0.5-mg/kg dose of dextromethorphan. Urine was collected for 8 hours after biomarker administration, and enzyme activity was assessed by use of previously validated caffeine and dextromethorphan molar ratios. CYP2D6 genotyping was also performed in 10 of 12 subjects with CF and 11 of 12 control subjects. There were no significant differences in the urinary molar ratios for any of the enzyme systems evaluated. These data suggest that CF does not alter the activities of CYP1A2, NAT-2, XO, and CYP2D6. Altered biotransformation of drugs in this patient population is likely enzyme- and isoform-specific and thus is apparent for only selected compounds that are substrates for enzymes other than CYP1A2, NAT-2, XO, and CYP2D6.

Arylamine N-Acetyltransferase↗

PubMed2003

Effects of NMDA receptor antagonists on acute mu-opioid analgesia in the rat.

Mixed research findings have led to a debate regarding the effect of N-methyl-D-aspartate (NMDA) receptor antagonists on opiate analgesia. NMDA antagonists have been found in various studies to enhance, to inhibit, or to have no effect on opiate analgesia. The present research used a single protocol to explore the effects of six NMDA receptor antagonists on acute morphine (3.0 mg/kg s.c.) and fentanyl (0.05 mg/kg s.c.) analgesia in adult male Sprague-Dawley rats. NMDA receptor antagonists were selected based on their abilities to block various sites on the NMDA receptor complex, including the noncompetitive antagonists MK-801 (0.1 and 0.3 mg/kg i.p.), dextromethorphan (10.0 and 30.0 mg/kg i.p.), and memantine (3.0 and 10.0 mg/kg i.p.), a glycine site antagonist, (+)-HA-966 (10.0 and 30.0 mg/kg i.p.), a competitive antagonist, LY235959 (1.0 and 3.0 mg/kg i.p.), and a polyamine site antagonist, ifenprodil (1.0 and 3.0 mg/kg i.p.). Analgesia was assessed using the tail-flick test. A single dose of each opiate was used. The low doses of the antagonists, which are known to produce significant neural and behavioral actions at NMDA receptors, had no effect on morphine or fentanyl analgesia. At the higher doses, morphine analgesia was significantly enhanced by LY235959 (3.0 mg/kg), and fentanyl analgesia was significantly enhanced by LY235959 (3.0 mg/kg), dextromethorphan (30.0 mg/kg), and (+)-HA-966 (30.0 mg/kg). Enhancement of analgesia occurred without any apparent adverse side effects. None of the NMDA antagonists affected tail-flick responses on their own, except the higher dose of LY235959 (3.0 mg/kg), which produced a mild analgesic effect. Because no consistent effects were observed, the data suggest that NMDA receptors are not involved in acute mu-opioid analgesia. The mechanisms underlying the enhancement of opiate analgesia by selected NMDA antagonists, such as LY235959, dextromethorphan, and (+)-HA-966, remain to be determined.

Analgesics, Opioid↗

PubMed2002

Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration.

The iboga alkaloid ibogaine and the novel iboga alkaloid congener 18-methoxycoronaridine are putative anti-addictive agents. Using patch-clamp methodology, the actions of ibogaine and 18-methoxycoronaridine at various neurotransmitter receptor ion-channel subtypes were determined. Both ibogaine and 18-methoxycoronaridine were antagonists at alpha 3 beta 4 nicotinic receptors and both agents were more potent at this site than at alpha 4 beta 2 nicotinic receptors or at NMDA or 5-HT(3) receptors; 18-methoxycoronaridine was more selective in this regard than ibogaine. In studies of morphine and methamphetamine self-administration, the effects of low dose combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan and of mecamylamine with dextromethorphan were assessed. Mecamylamine and dextromethorphan have also been shown to be antagonists at alpha 3 beta 4 nicotinic receptors. All three drug combinations decreased both morphine and methamphetamine self-administration at doses that were ineffective if administered alone. The data are consistent with the hypothesis that antagonism at alpha 3 beta 4 receptors is a potential mechanism to modulate drug seeking behavior. 18-Methoxycoronaridine apparently has greater selectivity for this site than other agents and may be the first of a new class of synthetic agents acting via this novel mechanism to produce a broad spectrum of anti-addictive activity.

Acetylcholine↗

PubMed1999

Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action.

Tricyclic antidepressants and carbamazepine have become the mainstay in the treatment of neuropathic pain. Within the last decade, controlled trials have shown that numerous other drugs relieve such pain. We identified all placebo-controlled trials and calculated numbers needed to treat (NNT) to obtain one patient with more than 50% pain relief in order to compare the efficacy with the current treatments, and to search for relations between mechanism of pain and drug action. In diabetic neuropathy, NNT was 1.4 in a study with optimal doses of the tricyclic antidepressant imipramine as compared to 2.4 in other studies on tricyclics. The NNT was 6.7 for selective serotonin reuptake inhibitors, 3.3 for carbamazepine, 10.0 for mexiletine, 3.7 for gabapentin, 1.9 for dextromethorphan, 3.4 for tramadol and levodopa and 5.9 for capsaicin. In postherpetic neuralgia, the NNT was 2.3 for tricyclics, 3.2 for gabapentin, 2.5 for oxycodone and 5.3 for capsaicin, whereas dextromethorphan was inactive. In peripheral nerve injury, NNT was 2.5 for tricyclics and 3.5 for capsaicin. In central pain, NNT was 2.5 for tricyclics and 3. 4 for carbamazepine, whereas selective serotonin reuptake inhibitors, mexiletine and dextromethorphan were inactive. There were no clear relations between mechanism of action of the drugs and the effect in distinct pain conditions or for single drug classes and different pain conditions. It is concluded that tricyclic antidepressants in optimal doses appear to be the most efficient treatment of neuropathic pain, but some of the other treatments may be important due to their better tolerability. Relations between drug and pain mechanisms may be elucidated by studies focusing on specific neuropathic pain phenomena such as pain paroxysms and touch-evoked pain.

Analgesics↗

PubMed2002

Displacement and nonlinear chromatographic techniques in the investigation of interaction of noncompetitive inhibitors with an immobilized alpha3beta4 nicotinic acetylcholine receptor liquid chromatographic stationary phase.

A liquid chromatographic column containing immobilized alpha3beta4 nicotinic acetylcholine receptors (alpha3beta4-nAChRs) has been used to determine the equilibrium association constants (Ka), desorption rate constants (kd), and adsorption rate constants (ka) for the noncompetitive inhibitors: mecamylamine, ketamine, bupropion, and dextromethorphan. Displacement chromatography, with mecamylamine as the displacer, was used to verify that the four compounds bound to the same site on the immobilized alpha3beta4-nAChRs. Nonlinear chromatographic techniques were then utilized to calculate the Ka, ka, and kd values associated with the formation of the noncompetitive inhibitor-alpha3beta4-nAChR complexes. The ka values determined in this study ranged from 19.7 to 10.5 microM(-1) sec(-1), with a relative order of mecamylamine > dextromethorphan > or = ketamine > bupropion. The kd values determined in this study indicated that dextromethorphan-induced inhibition should produce a longer recovery time than the other three NCIs. This was consistent with results from a previous in vitro study. The data from this study indicate that the immobilized alpha3beta4-nAChR column and nonlinear chromatography can be used in the study of NCIs at the alpha3beta4-nAChR.

Chromatography, Liquid↗

PubMed2003

Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine.

INTRODUCTION: Melperone, a butyrophenone neuroleptic, is frequently used for its sleep-inducing properties. Despite its common use for more than 30 years, it is not yet characterized regarding its effects on cytochrome P450 s (CYPs). In an open pilot study, effects of melperone on the steady-state blood levels of venlafaxine, a recently introduced serotonin- and noradrenaline reuptake inhibiting antidepressant, were assessed. METHODS: The dose-corrected serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed retrospectively in a therapeutic drug-monitoring (TDM) database comprising 94 patients. In addition, three patients received venlafaxine and melperone concomitantly and the serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed before, during, and after melperone co-medication. The effect of melperone on CYP2D6 was further assessed in seven patients by means of the dextromethorphan O-demethylation, which serves as a CYP2D6 probe reaction. RESULTS: Patients treated concomitantly with venlafaxine and melperone had significantly higher (mean +/- SD) venlafaxine (3.27 +/- 2.9 vs. 0.97 +/- 0.99 ng/ml per mg/d; p < 0.05) and lower O-desmethylvenlafaxine serum concentrations (0.69 +/- 0.35 vs. 1.51 +/- 0.9 ng/ml per mg/d; p < 0.01) compared to patients without melperone comedication. In the three patients, venlafaxine serum concentrations increased, on average by 52 % during melperone co-medication, whereas O-desmethylvenlafaxine was decreased, on average by 29 %. Administration of melperone over three days elevated the ratio of dextromethorphan to dextrorphan from 0.044 +/- 0.04 to 0.09 +/- 0.083 (p < 0.05). DISCUSSION: This study pointed to an inhibitory effect of melperone on the O-demethylation of venlafaxine. Because the O-demethylation of venlafaxine is almost exclusively catalyzed by CYP2D6 it is concluded that melperone is an inhibitor of CYP2D6. The hypothesis was further corroborated by the inhibitory effect of melperone on the dextromethorphan O-demethylation.

Adult↗

PubMed1995

High yield expression of functionally active human liver CYP2D6 in yeast cells.

In order to develop a model system for studying drug metabolism, we constructed recombinant yeast strains expressing human liver cytochromes P450. A high yield of cDNA-derived CYP2D6 was obtained, due to optimization of the initiation ATG codon context. The PCR-based site-mutagenesis method was used to introduce an AAA sequence immediately before the initiation codon resulting in increased translation of the GAL10-CYC1-derived mRNA. The use of a peptidase-deficient yeast strain also helped to increase the CYP2D6 content. A P450 content of 250 +/- 30 pmol per mg of microsomal protein was achieved. HPLC analysis confirmed that heterologously expressed CYP2D6 catalysed the oxidation of debrisoquine and dextromethorphan, two prototype substrates for CYP2D6. The Km for debrisoquine 4-hydroxylase was found to be 50 microM and Vmax 7.5 pmol mg-1 min-1. Dextromethorphan O-demethylase activity in CYP2D6-containing microsomes was characterized by Km 8.5 microM and Vmax 700 pmol mg-1 min-1. Biotransformation of debrisoquine and dextromethorphan was not detected in control microsomes. Yeast synthesizing CYP2D6 represents a useful in vitro system for studying xenobiotic metabolism.

Base Sequence↗

PubMed1993

Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone.

1. In microsomes prepared from three human livers, methadone competitively inhibited the O-demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty-two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O-demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.

Adolescent↗

PubMed1991

Effects of opiates on sodium excretion in the isolated perfused rat kidney.

1. A rat isolated perfused kidney preparation was utilized to define clearly a renal site of action. The variables measured were perfusate pressure and flow, glomerular filtration rate, urine volume, sodium excretion and potassium excretion. 2. Dextromethorphan (3 nmol/L) and dextrorphan (10 nmol/L) reduced sodium excretion in kidneys from rats on either control or high K+ diet, in the absence of any other measured renal effects. Dextromethorphan (10 nmol/L) produced a decrease in glomerular filtration rate as well as a decrease in sodium excretion. Naloxone (1 mumol/L) inhibited the effect of dextromethorphan on sodium excretion but had no effect when administered alone. 3. The levorotatory opiates levorphanol and levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion. 4. The results suggest a renal action specific for dextrorotatory opiates. This renal action is consistent with earlier binding studies suggesting preferential recognition of dextrorotatory opiates.

Animals↗

PubMed1999

Inhibitory effects of trospium chloride on cytochrome P450 enzymes in human liver microsomes.

Trospium chloride, an atropine derivative used for the treatment of urge incontinence, was tested for inhibitory effects on human cytochrome P450 enzymes. Metabolic activities were determined in liver microsomes from two donors using the following selective substrates: dextromethorphan (CYP2D6), denitronifedipine (CYP3A4), caffeine (CYP1A2), chlorzoxazone (CYP2E1), S-(+)-mephenytoin (CYP2C19), S-(-)-warfarin (CYP2C9) and coumarin (CYP2A6). Incubations with each substrate were carried out without a possible inhibitor and in the presence of trospium chloride at varying concentrations (37-3000 microM) at 37 degrees in 0.1 M KH2PO4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by high-performance liquid chromatography (HPLC) in all cases except CYP2A6 where direct fluorescence spectroscopy was used. First, trospium chloride IC50 values were determined for each substrate at respective K(M) concentrations. Trospium chloride did not show relevant inhibitory effects on the metabolism of most substrates (IC50 values considerably higher than 1 mM). The only clear inhibition was seen for the CYP2D6-dependent high-affinity O-demethylation of dextromethorphan, where IC50 values of 27 microM and 44 microM were observed. Therefore, additional dextromethorphan concentrations (0.4-2000 microM) were tested. Trospium chloride was a competitive inhibitor of the reaction with Ki values of 20 and 51 microM, respectively. Thus, trospium chloride has negligible inhibitory effects on CYP3A4, CYP1A2, CYP2E1, CYP2C19, CYP2C9 and CYP2A6 activity but is a reasonably potent inhibitor of CYP2D6 in vitro. Compared to therapeutic trospium chloride peak plasma concentrations below 50 nM, the 1000-times higher competitive inhibition constant Ki however suggests that inhibition of CYP2D6 by trospium chloride is without any clinical relevance.

Benzilates↗

PubMed2003

Substrate specificity and kinetic properties of seven heterologously expressed dog cytochromes p450.

Seven dog cytochromes p450 (p450s) were heterologously expressed in baculovirus-Sf21 insect cells. Of all enzymes examined, CYP1A1 exhibited high 7-ethoxyresorufin O-deethylase activity (low Km enzyme, 1 microM). CYP2B11 and CYP3A12 effectively catalyzed the N1-demethylation and C3-hydroxylation of diazepam (and its derivatives), whereas CYP3A12 and CYP2D15 catalyzed exclusively the N- and O-demethylation, respectively, of dextromethorphan. However, no saturation velocity curves for the N-demethylation of dextromethorphan (up to 500 microM) were achieved, suggesting a high Km for CYP3A12. In contrast to CYP3A12, the CYP2D15-dependent O-demethylation of dextromethorphan was a low Km process (Km = 0.7 microM), similar to that in dog liver microsomes (Km = 2.3 microM). CYP2D15 was also capable of metabolizing bufuralol (1'-hydroxylation), with a Km of 3.9 microM, consistent with that obtained with dog liver microsomes. CYP3A12 was shown to primarily oxidize testosterone at 16alpha-, 2alpha/2beta-, and 6beta-positions. Selectivity of CYP3A12 was observed toward testosterone 6beta-(Km = 83 microM) and 2alpha/2beta-hydroxylations (Km = 154 microM). However, the 16alpha-hydroxylation of testosterone was catalyzed by CYP2C21 also (Km = 6.4 microM for CYP2C21). Therefore, the 6beta- and 16alpha-hydroxylation of testosterone can potentially be employed as markers of CYP3A12 and CYP2C21 (at low concentration), respectively. CYP2C21 was also capable of catalyzing diclofenac 4'-hydroxylation, although some activity was detected with CYP2B11. Surprisingly, none of the p450s selectively metabolized (S)-mephenytoin 4'-hydroxylation. The results described herein are a first step toward the systematic evaluation of a panel of dog p450s and the development of dog p450 isoenzyme-selective marker substrates, as well as providing useful information on prediction and extrapolation of the results from in vitro to in vivo and from dog to human.

Animals↗

PubMed1989

Antitussive agents as N-methylaspartate antagonists: further studies.

The relative potencies of ketamine and the morphinan derivatives dextrorphan, dextromethorphan, and levorphanol as antagonists of the excitatory actions of N-methylaspartate on rat spinal neurones in vivo were examined, both following their microelectrophoretic administration and, with the exception of levorphanol, after intravenous injection. Applied microelectrophoretically, dextrorphan was a more potent N-methylaspartate antagonist than ketamine, levorphanol, or dextromethorphan. After systemic administration, however, dextrorphan was rather less potent than ketamine in this respect, whereas dextromethorphan remained less potent than either ketamine or dextrorphan. Noscapine, an antitussive that lacks anticonvulsant activity, failed to reduce selectively responses to N-methylaspartate as did papaverine, an isoquinoline structurally related to noscapine, and triprolidine, an antihistamine commonly found in proprietary cough medicines. The results are discussed with particular reference to the potential of the compounds tested as anticonvulsant and neuroprotective agents in vivo.

Animals↗

PubMed1999

Rapid characterization of the major drug-metabolizing human hepatic cytochrome P-450 enzymes expressed in Escherichia coli.

The major drug-metabolizing human hepatic cytochrome P-450s (CYPs; CYP1A2, 2C9, 2C19, 2D6, and 3A4) coexpressed functionally in Escherichia coli with human NADPH-P-450 reductase have been validated as surrogates to their counterparts in human liver microsomes (HLM) using automated technology. The dealkylation of ethoxyresorufin, dextromethorphan, and erythromycin were all shown to be specific reactions for CYP1A2, CYP2D6, and CYP3A4 that allowed direct comparison with kinetic data for HLM. For CYP2C9 and CYP2C19, the kinetics for the discrete oxidations of naproxen and diazepam were compared to data obtained using established, commercial CYP preparations. Turnover numbers of CYPs expressed in E. coli toward these substrates were generally equal to or even greater than those of the major commercial suppliers [CYP1A2 (ethoxyresorufin), E. coli 0.6 +/- 0.2 min(-1) versus B lymphoblasts 0.4 +/- 0.1 min(-1); CYP2C9 (naproxen), 6.7 +/- 0.9 versus 4.9 min(-1); CYP2C19 (diazepam), 3.7 +/- 0.3 versus 0.2 +/- 0.1 min(-1); CYP2D6 (dextromethorphan), 4.7 +/- 0.1 versus 4.4 +/- 0.1 min(-1); CYP3A4 (erythromycin), 3 +/- 1.2 versus 1.6 min(-1)]. The apparent K(m) values for the specific reactions were also similar (K(m) ranges for expressed CYPs and HLM were: ethoxyresorufin 0.5-1.0 microM, dextromethorphan 1.3-5.9 microM, and erythromycin 18-57 microM), indicating little if any effect of N-terminal modification on the E. coli-expressed CYPs. The data generated for all the probe substrates by HLM and recombinant CYPs also agreed well with literature values. In summary, E. coli-expressed CYPs appear faithful surrogates for the native (HLM) enzyme, and these data suggest that such recombinant enzymes may be suitable for predictive human metabolism studies.

Cytochrome P-450 Enzyme System↗

PubMed2001

In vivo effect of clarithromycin on multiple cytochrome P450s.

The in vivo effects of oral clarithromycin administration on the in vivo activity of cytochrome P450 1A2, 2C9, and 2D6 were determined. The cytochrome P450 probes caffeine (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) were administered as an oral cocktail prior to and 7 days after oral clarithromycin (500 mg twice daily) administration to 12 healthy male subjects. Blood and urine samples were collected and assayed for each of the compounds and their metabolites using high-performance liquid chromatography. The CYP1A2 indices, oral caffeine clearance (6.2 +/- 3.3 l/h before and 5.7 +/- 4.2 l/h after, p > 0.05) and the 6-h paraxanthine to caffeine serum concentration ratio (0.49 +/- 0.3 before and 0.44 +/- 0.3 after, p > 0.05), were unchanged following clarithromycin dosing. Neither the tolbutamide oral clearance (0.77 +/- 0.28 l/h before and 0.72 +/-0.24 l/h after, p > 0.05) nor the tolbutamide urinary metabolic ratio (779 +/- 294 before and 681 +/- 416 after, p > 0.05) indices of CYP2C9 were altered by clarithromycin administration. In the case of CYP2D6, the dextromethorphan to dextrorphan urinary ratio was not significantly different before (0.021 +/- 0.04) and after (0.024 +/- 0.06) clarithromycin dosing. In conclusion, clarithromycin does not appear to alter the in vivo catalytic activity of CYP1A2, CYP2C9, and CYP2D6 in healthy individuals as assessed by caffeine, tolbutamide, and dextromethorphan, respectively.

Adult↗