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R J Walker

Publications and source records attributed to R J Walker.

At least 55 records · Page 3Linked to original sources
PubMed1998

The actions of muscle relaxants at nicotinic acetylcholine receptor isoforms.

The pharmacological diversity of the different isoforms of the nicotinic acetylcholine receptor arises from the diversity of the subunits that assemble to form the native receptors. The aim of this study was to investigate the actions of the muscle relaxants d-tubocurarine, pancuronium and vecuronium on different isoforms of nicotinic acetylcholine receptors (mouse foetal muscle, mouse adult muscle and a rat neuronal), using the Xenopus oocyte expression system. Oocytes were injected with cRNAs for alpha, beta, gamma, delta subunits (the native foetal muscle subunit combination), or with cRNAs for alpha, beta, epsilon, delta subunits (the native adult muscle subunit combination), or with cRNAs for alpha4beta2 subunits (a putative native neuronal subunit combination). Acetylcholine had a similar potency at all three subunit combinations (EC50 11.6, 17.4 and 19.1 microM, respectively). At all three receptor types, d-tubocurarine and pancuronium blocked the responses elicited by acetylcholine in a reversible manner. Furthermore, the inhibition of the acetylcholine currents for the foetal and adult nicotinic acetylcholine receptor by pancuronium and d-tubocurarine was independent of the holding voltage over the range -100 to -40 mV. In oocytes expressing the foetal muscle nicotinic acetylcholine receptors the inhibition of the current in response to 100 microM acetylcholine by 10 nM d-tubocurarine was 29 +/- 5% (mean +/- S.E.M.; n = 7), and the inhibition by 10 nM pancuronium was 39 +/- 6% (mean +/- S.E.M.; n = 8; P > 0.05 vs. d-tubocurarine). However, in the adult form of the muscle nicotinic acetylcholine receptor, 10 nM d-tubocurarine and 10 nM pancuronium were both more effective at blocking the response to 100 microM acetylcholine compared to the foetal muscle nicotinic acetylcholine receptor, with values of 55 +/- 5% (P < 0.01; n = 12) and 60 +/- 4% (P < 0.001; n = 10), respectively. Thus the developmental switch from the gamma to the epsilon subunit alters the antagonism of the nicotinic acetylcholine receptor for both pancuronium and d-tubocurarine. Vecuronium was more potent than pancuronium. One nM vecuronium reduced the response to 100 microM acetylcholine by 71 +- 6% (n = 10) for foetal and 63 +/- 5% (n = 4) for adult nicotinic acetylcholine receptors. In the alpha4beta2 neuronal nicotinic acetylcholine receptor combination, 10 nM pancuronium was a more effective antagonist of the response to 100 microM acetylcholine (69 +/- 6%, n = 6) than 10 nM d-tubocurarine (30 +/- 5%; n = 6; P < 0.05 compared to pancuronium). This is in contrast to the adult muscle nicotinic acetylcholine receptor, where pancuronium and d-tubocurarine were equieffective. The expression of the beta2 subunit with muscle alpha, epsilon and delta subunits formed a functional receptor which was blocked by pancuronium and d-tubocurarine in a similar manner to the alphabeta1epsilondelta subunit consistent with the hypothesis that the beta subunit is not a major determinant in the action of this drug at the adult muscle nicotinic acetylcholine receptor.

Animals↗
PubMed1998

Evidence for the involvement of nitric oxide in the inhibitory effect of GSPYFVamide on Helix aspersa central neurones.

Intracellular recordings were made from neurones E-8, E-16 and E-13a in the visceral ganglion of Helix aspersa. GSPYFVamide inhibits the activity of these neurones and the role of a second messenger system in this inhibition was investigated. 8-Bromo-cGMP, 100 microM was found to potentiate this inhibition while ODQ, 100 microM, an inhibitor of guanylyl cyclase, almost completely blocked GSPYFVamide-induced inhibition. Four NO donors sodium nitroprusside, 100 microM, sodium nitrite, 1 mM, SNOG, 50 microM, and SNAP, 10-50 microM, all potentiated the GSPYFVamide-induced inhibition. L-NAME, 100-1000 microM, a competitive inhibitor of NOS, blocked the GSPYFVamide-induced inhibition. In some cases recovery was only partial. The possible role of NO in modulating the inhibitory response to GSPYFVamide is discussed.

Animals↗
PubMed1998

The role of cAMP in the actions of the peptide AF3 in the parasitic nematodes Ascaris suum and Ascaridia galli.

AF3 (AVPGVLRFamide) is an endogenous RFamide-like peptide isolated from the parasitic nematode Ascaris suum. It has a potent and long lasting excitatory effect in A. suum and Ascaridia galli. This is mediated by a mechanism independent of the nicotinic-like acetylcholine (ACh) receptor, which mediates excitatory transmission at the neuromuscular junction of both nematodes. In addition, AF3 has been found to sensitise A. suum muscle to the contractile effect of ACh. In this study, the involvement of the second messenger cAMP in mediating the action of AF3 on the somatic musculature of A. suum and A. galli has been investigated. Two approaches have been used; the effects of drugs which raise intracellular cAMP levels on the contractile responses to AF3 have been examined and biochemical assays have been used to measure the effects of AF3 on cAMP levels. AF3 contractions were inhibited in A. suum by 10 microM forskolin (by 22% of control; P < 0.05; n = 9) and by 500 microM isobutylmethylxanthine (IBMX, by 27% of control; P < 0.001; n = 6). AF3 decreased cAMP concentrations in A. suum somatic muscle (basal, 1721 +/- 134 pmol mg-1 protein; with 1 microM AF3, 1148 +/- 133 pmol mg-1 protein; P < 0.05, n = 5). AF3 (1 microM) also reduced the 10 microM forskolin induced potentiation of cAMP concentrations in A. suum (forskolin 3242 +/- 471 pmol mg-1 protein; forskolin and AF3, 1524 +/- 143 pmol mg-1 protein; P < 0.001, n = 6) and A. galli (forskolin 291 +/- 32 pmol mg-1 protein, forskolin +AF3, 185 +/- 12 pmol mg-1 protein; P < 0.005, n = 5). These data suggest that in both nematodes the contractile effect of AF3 is, at least in part, regulated by cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Venous endothelial changes in therapeutic arteriovenous fistulae.

Specimens of veins of therapeutic arteriovenous fistulae from five patients were examined by an en face immunohistochemical technique to investigate endothelial morphology and the presence of the vasoactive peptide endothelin-1 (ET-1). These were compared with control segments of long saphenous veins from six patients. Venous endothelium from the arteriovenous shunts was mostly intact even overlying phlebosclerotic plaques. Occasional small areas of denudation, with associated platelets, were present in the depressions of 'jet' lesion however. The endothelial cells were generally elongated and interspersed with foci of polyhedral cells. The control saphenous veins contained elongated endothelial cells without detectable denudation. Image analysis of histological sections of veins from the shunts indicated significantly less intact elastic tissue than control veins but greater mononucleated endothelial cell density in en face preparations. ET-1 staining was considerably stronger in endothelium from the fistulae than in the control saphenous veins and was most intense over the raised crescentic ridges of jet lesions, stenoses and phlebosclerotic plaques. Endothelial mitoses and cells with hyperchromatic nuclei stained more strongly for ET-1 than surrounding cells. These results indicate that the endothelial cells lining veins associated with arteriovenous fistulae are dynamically altered by the increased haemodynamic stresses associated with these shunts. Furthermore ET-1 may act as a localising factor associated with intimal thickening at sites of 'jet' lesions, stenosis and phlebosclerosis.

Adult↗
PubMed1998

The effect of FMRF-amide-like peptides on electrical activity in isolated mammalian spinal cord.

FMRFamide and seven FMRFamide-like peptides were manually synthesized on solid phase and their effects tested upon the amplitude of the dorsal root-ventral root monosynaptic reflex (MSR) and dorsal horn field potentials (FP) in an isolated preparation of rat spinal cord. FLFQPQRFamide (NPFF) and AGEGLSSPFWSLAAPQRFamide (NPAF) both depressed a fast component of the FP with similar potencies. FMRFamide also inhibited the FP but its potency was much lower. NPFF and NPAF potentiated the amplitude of the MSR while FMRFamide had no effect. PQRFamide, PFRFamide, FFRFamide, DPQRFamide and Fmoc-FLFQPQRFamide were also examined on the MSR. PQRFamide and PFRFamide potentiated the MSR whereas FFRFamide and DPQRFamide caused a small depression at high concentrations. The increase in amplitude of the MSR induced by NPFF was completely abolished when the N-terminal was left protected with an Fmoc-group. The results suggest that PFRFamide and PQRFamide may act as agonists of NPFF and NPAF whereas the other peptides did not show such activity.

Amino Acid Sequence↗
PubMed1998

Comparison of responses of spontaneously active cells in the cerebellar Purkinje layer to parallel fibre stimulation in slice preparations and urethane-anaesthetised rats: effects of benzodiazepine receptor ligands.

1. GABA-mediated inhibitory responses were induced in spontaneously active Purkinje cells by parallel fibre stimulation in cerebellar slices or in urethane-anaesthetised rats. Effects of agonist and inverse agonist benzodiazepine (BDZ) receptor ligands were compared in the preparations. 2. Purkinje cells fired simple spikes at higher rates in slice preparations while complex spikes were seldom (in vivo) or never observed (slice). Cells fired more regularly in vivo resulting in the occurrence of rhythmic postinhibitory responses in the PSTH analysis in some preparations. 3. Single pulse stimulation of parallel fibres at just suprathreshold intensity induced inhibition of Purkinje cell activity in both preparations. At lower firing rates there was a marked increase in the duration of this response, which was more evident in vivo where more slowly firing cells were encountered. 4. BDZ receptor ligands modified inhibitory responses in slice preparations with only weak effects on the firing rates of the cells. These compounds predominately induced changes in firing rate in the anaesthetised rat with little evidence of direct modification of GABA-mediated synaptic transmission. 5. In a few experiments, following injection of the partial inverse agonists beta-CCE and beta-CCM, block of the inhibitory response was observed independent of changes in firing rate. Bidirectional efficacy of BDZ receptor ligand (agonists decrease firing and increase inhibitory response, inverse agonists increase firing and decrease inhibitory response) was demonstrated for modulation of inhibitory responses in slices and for changes in firing rate in vivo. The increased firing rate response in vivo was biphasic the magnitude of the later phase being correlated with efficacy of inverse agonists. 6. It is concluded that cerebellar slice preparations are more appropriate for studying direct effects of BDZ receptor ligands on GABA-mediated synaptic inhibition than in vivo preparations.

Action Potentials↗
PubMed1998

Structural requirements and ionic mechanism of the Mytilus inhibitory peptides (MIPs) on Helix central neurons.

1. The structural and ionic requirements for potent FVamide-induced inhibition were investigated using Helix aspersa central neurons under current or voltage clamp. 2. For potent FVamide inhibition the full hexapeptide sequence, GSPYFVamide, was required. The rank order of decreasing potency was GSPYFVamide >> SPYFVamide> PYFVamide > YFVamide. 3. GSPYFVamide inhibition involved an increase in conductance to both potassium and chloride ions as demonstrated by ion substitution experiments and addition of 4-aminopyridine, tetraethylammonium, 4,4-di-isothiocyanatostilbene-2,2'-disulfonic acid, 4,4-dinitrostilbene-2,2'-disulfonic acid disodium salt and furosemide to the solution bathing the preparation.

Animals↗
PubMed1998

Cellular and molecular mechanisms of nitric oxide-induced heart muscle relaxation.

1. The nitric oxide (NO) donor S-nitro-N-acetyl-penicillamine (SNAP) inhibits Helix aspersa heart activity and relaxes muscles. 2. K-free saline and ouabain both depress SNAP-induced relaxation in most experiments, but in a few preparations they either had no effect or potentiated SNAP-induced relaxation. 3. Na-K pump reactivation following preincubation in K-free saline leads to the pronounced transient relaxation of heart muscle, the magnitude of which depends on the duration of preincubation. 4. 0.1 mM SNAP inhibited the ouabain sensitive part of 86Rb uptake, which reflects Na-K pump activity. This inhibition is potentiated by phospholipase C. 5. SNAP increased cGMP levels in the heart. 6. These results indicate that SNAP-induced relaxation depends on Na and Ca gradients across the membrane, which suggests that Na:Ca exchange is involved in the mechanisms of SNAP-induced relaxation. It is postulated that SNAP elicits its inhibitory effect on the heart through a cGMP-dependent Na:Ca exchange.

Animals↗
PubMed1998

Tenoxicam does not alter renal function during anaesthesia in normal individuals.

BACKGROUND: Anaesthesia and surgery alter renal function. Inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs (NSAIDs) administered with anaesthesia may further compromise renal function. AIM: To study the effects of tenoxicam (NSAID) administered immediately prior to anaesthesia on renal function in normal individuals undergoing routine surgery. METHODS: A randomised single blind placebo controlled study comparing tenoxicam (40 mg intravenously) with placebo was carried out in 20 healthy (ASA I) patients undergoing lower spinal surgery. Glomerular filtration rate (GFR) was determined by creatinine clearance and renal tubular function measured as osmolar and free water clearance. RESULTS: GFR fell by 60% at the end of surgery but returned to pre-operative values by six hours post-operatively. There was no difference between placebo or tenoxicam with regard to changes in GFR. Tubular function was not altered by tenoxicam. CONCLUSIONS: Current clinical practice of using NSAIDs for post-operative analgesia in low risk individuals appears to have no adverse effects on renal function.

Adult↗
PubMed1997

A human gene encoding morphine modulating peptides related to NPFF and FMRFamide.

FMRFamide-related peptides have been isolated from both invertebrates and vertebrates and exhibit a wide range of biological effects in rats. We show here that in humans 2 FMRFamide-related peptides are encoded by a single gene expressed as a spliced mRNA. The larger predicted peptide (AGEGLNSQFWSLAAPQRFamide) differs from the peptide isolated from bovines (AGEGLSSPFWSLAAPQRFamide) by the substitutions of 2 amino acids. The shorter predicted peptide (NPSF, SQAFLFQPQRFamide) is 3 amino acids longer than the bovine 8 amino-acid NPFF (FLFQPQRFamide) or the human NPFF peptide isolated from serum [5], suggesting that the encoded protein is subject to cleavage by a tripeptidyl peptidase or by a novel processing mechanism. On rat spinal cord, the larger peptide is indistinguishable in activity from the equivalent bovine peptide whereas the smaller extended peptide is inactive.

Action Potentials↗
PubMed1997

Europa's magnetic signature: report from Galileo's pass on 19 December 1996.

On 19 December 1996 as Galileo passed close to Jupiter's moon, Europa, the magnetometer measured substantial departures from the slowly varying background field of Jupiter's magnetosphere. Currents coupling Europa to Jupiter's magnetospheric plasma could produce perturbations of the observed size. However, the trend of the field perturbations is here modeled as the signature of a Europa-centered dipole moment whose maximum surface magnitude is approximately 240 nanotesla, giving a rough upper limit to the internal field. The dipole orientation is oblique to Europa's spin axis. This orientation may not be probable for a field generated by a core dynamo, but higher order multipoles may be important as they are at Uranus and Neptune. Although the data can be modeled as contributions of an internal field of Europa, they do not confirm its existence. The dipole orientation is also oblique to the imposed field of Jupiter and thus not directly produced as a response to that field. Close to Europa, plasma currents appear to produce perturbations with scale sizes that are small compared with a Europa radius.

Extraterrestrial Environment↗
PubMed1997

Isolation of bioactive compounds from Helix aspersa nerve tissue and the effect of pQPPLPRYamide on heart, esophagus and central neurons of H. aspersa and rectum of Anodonta woodiana.

1. Both acetone and methanol extraction was used to isolate bioactive compounds from 1000 Helix aspersa brains. 2. Seven compounds were isolated of which four were identified as follows: Ha-1, 5-hydroxytryptamine; Ha-3, GSPYFVamide; Ha-4, pQPPLPRYamide; Ha-5, SGYLAFPRMamide. There was insufficient material to identify Ha-2, Ha-6 and Ha-7. 3. Ha-4, pQPPLPRYamide, was found to excite the heart of H. aspersa, relax the esophagus and both excite (mainly) and inhibit central neurons. In addition, this peptide contracted the rectum of Anodonta woodiana. 4. It is concluded that pQPPLPRYamide is an example of a new molluscan peptide family, designated as PRYamide.

Animals↗
PubMed1997

The effects of the peptides AF3 (AVPGVLRFamide) and AF4 (GDVPGVLRFamide) on the somatic muscle of the parasitic nematodes Ascaris suum and Ascaridia galli.

AF3 (AVPGVLRFamide) and AF4 (GDVPGVLRFamide) are endogenous RFamide-like peptides isolated from the parasitic nematode Ascaris suum. Here the actions of these peptides on the somatic musculature of Ascaris have been investigated and compared to the action of acetylcholine (ACh), the excitatory transmitter at the neuromuscular junction. ACh, AF3 and AF4 contracted muscle with EC50S of 13 +/- 1 microM, 24 +/- 6 nM and 37 +/- 2 nM, respectively (n = 6). The muscle cells were depolarized by ACh (3 microM; 5.2 +/- 0.4 mV, n = 42), AF3 (1 microM; 2.6 +/- 0.3 mV, n = 19) and AF4 (1 microM; 3.3 +/- 0.4 mV, n = 19). EC50S were 681 +/- 329 nM (AF3) and 901 +/- 229 nM (AF4), but an estimate could not be made for ACh due to muscle contraction at concentrations greater than 10 microM. The depolarization to 3 microM ACh was abolished by the nicotinic receptor antagonist mecamylamine (10 microM; n = 5) but the responses to the peptides were not (111 +/- 7% and 108 +/- 17% with respect to control; n = 5). The depolarization elicited by ACh was reduced to a greater extent by a 50% reduction in extracellular Na+ concentration than the response to AF3 and AF4 (P < 0.02). Cobalt was more effective at blocking the AF3 and AF4 depolarizations than those to ACh. These observations suggest that AF3 and AF4 contract Ascaris muscle without an action at the Ascaris nicotinic receptor. Furthermore, the ionic mechanism through which AF3 and AF4 depolarize Ascaris muscle is different from that for ACh. ACh, AF3 and AF4 were also found to contract Ascaridia galli somatic muscle with EC50S of 13 +/- 3 microM, 721 +/- 236 nM and 371 +/- 177 nM, respectively (n = 7). The muscle cells were depolarized by ACh (EC50 = 14 +/- 5 microM, n = 5), AF3 (EC50 = 5 +/- 3 microM, n = 4) and AF4 (EC50 = 10 +/- 5 microM, n = 4). Therefore the response to these peptides is not unique to Ascaris and they may subserve a functional role in the motor nervous system of parasitic nematodes.

Acetylcholine↗
PubMed1997

Actions of the anthelmintic ivermectin on the pharyngeal muscle of the parasitic nematode, Ascaris suum.

The anthelmintic invermectin has a number of effects on nematodes which result in changes in behaviour, particularly locomotion, including paralysis and an inhibition of feeding. This paper describes the application of an in vitro pharmacological approach to further delineate the action of ivermectin on feeding behaviour. Contraction of Ascaris suum pharyngeal muscle was monitored using a modified pressure transducer system which detects changes in intrapharyngeal pressure and therefore contraction of the radial muscle of the pharynx. The pharynx did not contract spontaneously. However, serotonin (5-HT, 100 microM) stimulated rhythmic contractions and relaxations (pumping) at a frequency of 0.5 Hz. gamma-Aminobutyric acid (GABA) and glutamic acid inhibited the pumping elicited by 5-HT. The duration of inhibition was concentration dependent (1-1000 microM) with a threshold of 1 microM and 10 microM respectively (n = 8). Ivermectin also inhibited pharyngeal pumping (1-1000 nM). At lower concentrations, ivermectin (1-10 pM) potentiated the GABA and glutamate inhibition, so that inhibition occurred at concentrations which were below threshold in the absence of ivermectin. These data provide evidence that the pharynx is a site for the action of ivermectin. Thus interruption of pharyngeal processes such as, feeding, regulation of hydrostatic pressure and secretion may provide a new site of anthelmintic action.

Animals↗
PubMed1997

The effects of the peptide KPNFIRFamide (PF4) on the somatic muscle cells of the parasitic nematode Ascaris suum.

1. Commonly used anthelmintic agents act on the muscle cells of parasitic nematodes to cause paralysis of the parasite and its expulsion from the host. 2. The motonervous system of nematodes contains neuropeptides, many of which are myoactive and elicit prolonged worm paralysis. Here we describe the actions of a novel peptide, KPNFIRFamide (Lys-Pro-Asn-Phe-Ileu-Arg-Phe-amide; PF4), which mediates relaxation of the somatic muscle of the parasitic nematode Ascaris suum. Its mechanism of action is compared to that of the inhibitory neuromuscular junction transmitter, gamma-aminobutyric acid (GABA), which gates a chloride channel on Ascaris muscle. 3. Both PF4 and GABA hyperpolarized the muscle cells (EC50 values 98 nM and 59 microM, respectively; n = 6) and this was accompanied by an increase in input conductance. 4. The increase in input conductance elicited by PF4 and a supramaximal concentration of GABA were additive (10 microM PF4, 7.78 +/- 1.88 microS; 10 mM GABA, 4.68 +/- 1.39 microS; 10 mM GABA and 10 microM PF4 12.05 +/- 2.6 microS, n = 6, P < 0.02 with respect to PF4 alone; P < 0.01 with respect to GABA alone). 5. The membrane potential response to 10 microM PF4 initially consisted of a fast hyperpolarization that occurred within 1 min of PF4 application. The reversal potential for this early response to PF4 (PF4-early) was determined at different extracellular chloride concentrations. Linear regression analysis of the natural logarithm of the extracellular chloride concentration against the reversal potential for PF4-early yielded a straight line with a slope of -29.6 +/- 2.4 (-34.4 to -24.9, 95% confidence limits; r2 = 0.82). This is close to the slope of -26.5 for a chloride-dependent event, as predicted by the Nernst equation. There was a significant correlation between the reversal potential for this event and the reversal potential for GABA (r = 0.94; P < 0.001; n = 12). 6. The late response to PF4 (PF4-late) appeared after 1 min and consisted of a slow reduction in the hyperpolarization to a plateau level, before the return of the membrane potential to the resting value. PF4-late is not likely to be a chloride-dependent event as during the hyperpolarization caused by a supramaximal concentration of GABA the muscle cells depolarized when a supramaximal concentration of PF4 was added to the perfusate. The membrane potential in the presence of 1 mM GABA was -61.8 +/- 4.8 mV and in the presence of 1 mM GABA with 10 microM PF4 was -47.5 +/- 1.5 mV (P < 0.02; n = 6). 7. The conductance increase elicited by 30 microM GABA was blocked by 10 microM ivermectin (before ivermectin 0.97 +/- 0.2 microS, after ivermectin 0.33 +/- 0.12 microS; n = 5; P < 0.05; Student's paired t test) but the conductance increase elicited by 1 microM PF4 was not (before ivermectin 0.96 +/- 0.14 microS, after ivermectin 1.07 +/- 0.19 microS; n = 0.34; Student's paired t test). 8. These data indicate that PF4 elicits a potent, inhibition of Ascaris muscle cells which is partially mediated by chloride and which is independent of the inhibitory GABA receptor.

Animals↗
PubMed1997

Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine.

AIMS: Our previous studies using in vitro hepatic microsomal preparations suggested that the hepatic metabolism of quinine to form the major metabolite 3-hydroxyquinine is most likely catalysed by human P450 3A (CYP3A). The present study was carried out to investigate the kinetics and to identify and further characterise the human liver CYP isoforms involved in the metabolism of quinine. METHODS: In vitro human microsomal techniques were employed. RESULTS: The mean apparent Km value for 3-hydroxyquinine formation was 83 +/- 19 (s.d.) microM, ranging from 57 microM to 123 microM in microsomes from ten human livers. There was a 6.7-fold variation in Vmax values (mean 547 +/- 416 pmol min-1 mg-1). Quinine 3-hydroxylation was inhibited by the specific CYP3A inhibitors, troleandomycin, midazolam and erythromycin. Inhibitors selective for CYP1A1/2, CYP2D6, CYP2E1, CYP2C9/10 or CYP2C19 had little or no effect on quinine 3-hydroxylation. Using microsomes from a panel of livers, significant correlations were found only between 3-hydroxyquinine activity and other CYP3A activities (caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) and immunoreactive CYP3A content. There were no statistically significant correlation with activities selective for CYP1A2, CYP2C9 and CYP2E1. Competitive inhibition of quinine 3-hydroxylation was observed with a substrate known to be specifically metabolized by human CYP3A, i.e. midazolam, with an apparent Ki value of 11.0 microM. CONCLUSIONS: The present results strongly indicate that the conversion of quinine to 3-hydroxyquinine is the major metabolic pathway in human liver in vitro and that the reaction is catalysed by CYP3A isoforms.

Antimalarials↗