R.R. Shah

Genetic polymorphism of phenformin 4-hydroxylation

The ability to oxidize a single 50‐mg dose of phenformin to its 4‐hydroxy metabolite was determined in 195 individuals. Variations in the urinary ratio of phenformin/4‐hydroxyphenformin ranged from 1 to 184. Family studies were consistent with the hypothesis that this variability resulted from a single gene mode of inheritance in which impaired hydroxylation of phenformin appears as an autosomal recessive trait. Both genotype frequencies and the degree of dominance of the extensive metabolizer phenotype over the recessive showed a remarkable resemblance to those described for debrisoquine 4‐hydroxylation, which was confirmed by the high degree of correlation (rs = 0.785, P < 0.0001) between the phenformin ratio and the debrisoquine metabolic ratio. Such close agreement between the metabolism of these drugs may indicate that the same genetic control is in operation. Such genetic polymorphism of phenformin hydroxylation may have important implications for therapeutic response and for the possibility of toxic effects in a few individuals.

Influence of oxidation polymorphism on phenformin kinetics and dynamics

Plasma and urinary kinetics and responses of blood lactate, pyruvate, and glucose after a single 50‐mg phenformin dose were investigated in eight subjects of known debrisoquin oxidation phenotype, four poor metabolizers (PM) and four extensive metabolizers (EM). Higher peak plasma concentrations of phenformin (152.2 ± 12.7 ng/ml; mean ± SE) and a greater plasma AUC (779 ± 99 ng · hr · ml−1) were reached in PM than in EM (99.8 ± 13.7 ng/ml and 549 ± 47 ng · hr · ml−1). Although the urinary excretion of unchanged phenformin was greater in PM between 2 and 24 hr after dosing than in EM, excretion of 4‐hydroxy‐phenformin could not be detected in most samples collected from PM but was present in every sample from EM. Blood lactate concentrations increased dramatically in PM but fell in EM after phenformin. There were no changes in either blood pyruvate or glucose levels. The results may help to explain lactic acidosis in patients given phenformin in the absence of other predisposing factors.

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infection-induced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

Lack of congruence of S-carboxymethyl-L-cysteine sulphoxidation and debrisoquine 4-hydroxylation in a Caucasian population

One-hundred-and-twenty volunteers and three families were investigated for possible association between the sulphoxidation of S-carboxymethyl-L-cysteine and the debrisoquine hydroxylation polymorphism. The observed individual variations in these two metabolic reactions were shown not to be concordant (rs = 0.068) and any heritable factors controlling the major aspects of these phenomena do not co-segregate.

Prediction of subclinical perhexiline neuropathy in a patient with inborn error of debrisoquine hydroxylation

ic parameters and without signs of left ventricular failure. Thus the acute pulmonary hypertension seemed to be a major factor only in the contralateral, but not in the ipsilateral, reexpansion pulmonary edema. The identity of bilateral pressure measurements in our patient makes doubtful the earlier hypothesis concerning the inequalities in capillary or venous pressures in the two sides of the lungs.14, I5 We also ruled out positional-gravitational factors15, I6 by changing our patient’s position frequently, which did not influence the chest x-ray findings. As mentioned above, only rarely was a postpneumothorax pulmonary edema associated with the clinical picture of marked respiratory distress. Our patient, however, exhibited clinical symptoms of severe respiratory insufficiency and extremely low Pa,+ values, the x-ray picture revealed pulmonary edema, and there was no left ventricular failure. Thus the criteria for adult respiratory distress syndrome were fulfilled.13 The importance of hemodynamic measurements for diagnosing this syndrome in patients with bilateral pulmonary edema and for application of proper therapy is well established.‘3,17 Our report not only presents a new and unusual form of unilateral noncardiac edema alternating sequentially in the two lungs but stresses again the importance of hemodynamic measurements in a clinical entity in which the pathophysiology may be obscure.@

On the urinary disposition of phenformin and 4-hydroxy-phenformin and their rapid simultaneous measurement

more specific binding: n is small and the sites are saturated. The second negative slope corresponds with the binding to the second class of sites which are of lower affinity but in greater number; these sites are not saturable. These Scatchard plots are in complete disagreement with those obtained previously by Judis whose positive Scatchard plots indicate that n and/or Ka decrease as the protein concentration increases. One could attribute (Bowmer & Lindup 1978) this phenomenon of positive slopes to the contaminants of the albumin commercial preparation, like fatty acids or tryptophan. We have used simultaneously a normal albumin and an albumin free from fatty acids with no change in the binding percentage. The phenomenon of positive slope can also be attributed to a cooperative binding. This would be obvious when the protein concentration increases. The Scatchard plot of methadone is the same for a 0.40/, albumin or 404, albumin: n is only a little smaller for the 4% albumin, this could be due to the masking of some sites by the folding of the protein molecules. December 10, 1979

The metabolism of debrisoquine in man: (1) Regioselectivity of hydroxylation and (2) aberrant oxidative metabolism in two sibling patients with carbimazole-induced agranulocytosis

The regioselectivity of the metabolic hydroxylation of debrisoquine has been determined in 43 healthy British white volunteers and the priority was found to be in the order 4 greater than 7 greater than 6 greater than 5 greater than 8. The order of preference for hydroxylation position was independent of debrisoquine 4-hydroxylation phenotype. The extent of total aromatic hydroxylation varied widely between individuals and was largely independent of the extent of 4-hydroxylation, and thus of the influence of the DH/DL locus. Two sisters and their blood relations all excreted comparatively large amounts of the phenolic metabolites in their urine, indicating some genetic basis for the control of aromatic oxidation of debrisoquine in man. These same two sisters had previously developed agranulocytosis in association with carbimazole therapy.

The metabolism of S-carboxymethyl-L-cysteine in man: isolation of an ester glucuronic acid conjugate from urine

A conjugate isolated from urine of human volunteers after an oral dose of S-carboxymethyl-L-cysteine was characterized as a carboxylic acid ester glucuronide. Of the 166 volunteers investigated, 61 gave no detectable drug glucuronide (less than 0.5% administered dose); the remaining 105 showed a unimodal distribution of drug glucuronide excretion accounting for 0.5-11.5% (mean 4.1%, median 3.4%) of the total dose recovered in the 0-8 h urine. No significant variation in subject age, sex or urinary pH was observed between the two groups, but those not excreting urinary glucuronide had significantly higher 0-8 h urine volumes (P less than 0.001), although notable exceptions occurred.

Changes in Debrisoquine Hydroxylation Capacity Following Liver Surgery

Liver transplantation or the surgical construction of portacaval shunts may radically alter an individuals debrisoquine hydroxylation capacity. Good clinical management should encompass a full awareness of such changing needs and problems in patients who undergo hepatic surgery.